Abstract
Stephen G Waxman speaks to Roshaine Gunawardana, Commissioning Editor: Stephen G Waxman is the Bridget Marie Flaherty Professor of Neurology, Neurobiology and Pharmacology; Director, Center for Neuroscience and Regeneration/Neurorehabilitation Research, Yale University School of Medicine and Veterans Affairs Medical Center, CT, USA.
Q Your initial research began in examining the ion-channel architecture of myelinated axons. How did these studies lead to your interest in the field of pain?
I have tended to approach research from a mechanism-based and molecule-based perspective. I had worked, as a student, with Patrick Wall at University College London, UK in the late 1960s; but I then spent many years studying the molecular neurobiology, biophysics and physiology of ion channels. In the mid-1990s, we asked “Does axonal injury trigger a reprogramming of ion channel gene expression?” We saw substantial changes in sodium channel expression following axonal injury of dorsal root ganglion (DRG) neurons, and the potential relevance to pain was quite apparent.
Q In your opinion, how important was the genomic revolution in providing researchers with new tools to aid in the finding of novel therapeutic options for neurological injury?
I believe I may have been the first to use the term ‘genomic revolution‘, and I truly believe that it has been a revolution. As a result of new technologies, largely based on molecular biology and genomics, we can probe the genome and also ask proteomic questions in a way that is highly relevant to function. So we are in a position to assess, molecule by molecule, the players that shape function of the normal nervous system, as well as the injured nervous system. The genomic revolution was especially important in providing techniques that are highly specific and precise; we can move forward with speed that was previously unimaginable. It is all very exciting.
Q Your previous research has enabled you to make vital discoveries regarding how to explain the sensation of pain after nerve injury. Could you give me a brief outline of your findings?
Broadly speaking, we have learned a number of important lessons: first, we understand that, following nerve injury, there are changes in the expression of various sodium channel subtypes in the injured DRG neurons. This, in itself, contributes to hyperexcitability. Second, we understand that, in addition to the sodium channels themselves, there may also be changes in the expression of partner molecules, which interact with sodium channels and modulate their function. This, too, may contribute to hyperexcitability. Importantly, we and others have learned that there are three sodium channel subtypes that are preferentially expressed within DRG neurons, at levels much higher than in the CNS or heart. These sodium channel subtypes, Nav1.7, Nav1.8 and Nav1.9, are now major targets in the search for new pharmacotherapeutics that will mute hyperexcitability in injured DRG neurons, with minimal or no CNS or cardiac side effects. Hopefully, we will soon have a new generation of novel pharmacotherapies for pain.
Q How groundbreaking were the molecule-to-man studies you conducted along with your colleagues, in order to demonstrate the role of ion channels in human pain?
As a clinician–scientist, I have always been interested in the translational leap from molecule to man. This is what propelled us, in the first place, to launch a worldwide search for families with inherited neuropathic pain. When we found the first families with inherited erythromelalgia, and learned that they housed gain-of-function mutations of Nav1.7, a sodium channel that is preferentially expressed within DRG neurons and drives their firing, it was very exciting. We had, in fact, done the original functional profiling of wild-type Nav1.7 several years previously, so it was relatively straightforward to build on this as we unraveled the role of mutant Nav1.7 channels in inherited erythromelalgia.
I feel a very real sense of connectedness to people with inherited erythromelalgia and other Nav1.7-associated pain disorders. They have given us a very special gift, of their DNA and family histories. The lessons we have learned may help us to develop therapies that will help people with many forms of pain. But we feel a special responsibility to deliver more effective therapies to the people who have helped us. In a sense, these people have given us an enhanced sense of mission.
Q Recently, you have led an international coalition in studies on peripheral neuropathy. What were the main findings of this collaboration?
In my view, it is not quite correct to say that I ‘led‘ an international coalition. I was one of several individuals that put this coalition together. It has been, from my perspective, a model of a fruitful collaboration, and it has been fun! A collaborative approach – laboratory scientists and very astute clinicians working as a team – has recently enabled us to extend our studies, from rare genetic syndromes to common disorders. In these studies, we have found that gain-of-function variants of Nav1.7 are present in approximately 30% of patients with small fiber neuropathy – a very common disorder – with no other apparent cause. The small fiber neuropathy variants of Nav1.7 are quite different from the Nav1.7 mutations that cause erythromelalgia. But, again, they suggest a well-defined therapeutic target.
Q How well do you think basic research is being translated into clinical practice in the pain management field?
Basic scientists, clinical investigators and translational researchers are all moving ahead in a very exciting way; they are, from my perspective, talking with each other, which is very important. So, in concept, translation is occurring rapidly. Nonetheless, there are inherent challenges in translation and in clinical research. The available animal models are not predictive of efficacy in human pain. Moreover, clinical study can be complicated by placebo effects, and there is no biomarker for pain at this time. Hopefully, new imaging protocols will allow us to overcome this latter challenge. Taken as a whole, translation is a big step, and a challenging one. But, in a sense, that makes it a more exciting goal.
Q What plans do you have for further investigation and research in the future?
My team and I are very interested in ‘outlier‘ patients who house sodium channel variants or mutations and unusual pain syndromes. Why do some patients with erythromelalgia, for example, house Nav1.7 mutations throughout life, but manifest disease in adulthood? What protects these patients from pain at earlier ages? Why are occasional families quite sensitive to various drugs? Can this provide lessons that may be helpful in the development of personalized, genomically-based therapies? Do mutations or variants of other sodium channel subtypes, or other types of ion channels, contribute to pain? In addition, my laboratory is examining the molecular basis for pain using a number of different models involving nerve injury, spinal cord injury, diabetes and peripheral tissue injury including burn injury. I am fortunate to have wonderful colleagues, and we are moving ahead on all of these axes as rapidly as we can.
Financial & competing interests disclosure
SG Waxman has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.