Stephen Waxman, MD, PhD

  • Bridget M. Flaherty Professor of Neurology
  • Director, Center for Neuroscience and Regeneration Research

Stephen G. Waxman, MD, PhD

Stephen Waxman exemplifies the bridge between basic research and clinical medicine. He is the Bridget Flaherty Professor of Neurology, Neurobiology, and Pharmacology at Yale University. He served as Chairman of Neurology at Yale from 1986 until 2009. He founded and is Director of the Neuroscience & Regeneration Research Center at Yale. He also holds an appointment as Visiting Professor at University College London. Prior to moving to Yale, Dr. Waxman worked at Harvard, MIT, and Stanford.

Dr. Waxman received his BA from Harvard, and his MD and PhD degrees from Albert Einstein College of Medicine. His research, which uses tools from the “molecular revolution” to find new therapies that will promote recovery of function after injury to the brain, spinal cord, and peripheral nerves, has received international recognition.

Dr. Waxman’s research has defined the ion channel architecture of nerve fibers, and demonstrated its importance for axonal conduction (Science, 1985). He demonstrated increased expression of sodium channels in demyelinated axons (Science, 1982), identified the channel isoforms responsible for this remarkable neuronal plasticity which supports remission in multiple sclerosis (PNAS, 2004), and delineated the roles of sodium channels in axonal degeneration (PNAS, 1993). He has made pivotal discoveries that explain pain after nerve injury. Most recently, in translational leaps from laboratory to humans, he carried out molecule-to-man studies combining molecular genetics, molecular biology, and biophysics to demonstrate the contribution of ion channels to human pain (Trends in Molec.Med, 2005; PNAS, 2006), led an international coalition that identified sodium channel mutations as causes of peripheral neuropathy (PNAS, 2012) and has used atomic-level modeling to advance pharmacogenomics (Nature Comm., 2012). A new class of pain medications without central side-effects or addictive potential, based on his work, is currently in clinical trials.

Dr. Waxman has published more than 600 scientific papers. He has as edited nine books, and is the author of Spinal Cord Compression and of Clinical Neuroanatomy (translated into eight languages). He has served on the editorial boards of many journals including The Journal of Physiology, Brain, Annals of Neurology, Trends in Neurosciences, Nature Reviews Neurology, and Trends in Molecular Medicine, and is Editor-in-Chief of Neuroscience Letters. He has trained more than 150 academic neurologists and neuroscientists who lead research teams around the world.

A member of the Institute of Medicine of the National Academy of Sciences, Dr. Waxman’s many awards include the Tuve Award (NIH), the Distinguished Alumnus Award (Albert Einstein College of Medicine), the Dystel Prize and Wartenberg Award (American Academy of Neurology), and the Middleton Award and Magnuson Award of the Veterans Administration. He received the Annual Prize of the British Physiological Society, an honor he shares with his heroes, Nobel Prize laureates Andrew Huxley, John Eccles, and Alan Hodgkin.

4/17/13

Research interests
Axons; Electrophysiology; Ion Channels; Multiple Sclerosis; Neurology; Neurosciences; Sodium Channels; Stroke
Research summary

My research program focuses on the application of molecular techniques to the study of neurological diseases, especially spinal cord injury, multiple sclerosis, and neuropathic pain. We are interested in understanding the molecular basis for functional recovery after CNS injury. Our studies on ion channels in impulse conduction in normal, demyelinated, and regenerating nerve fibers use molecular biological, immunoultrastructural, pharmacological, and patch-clamp techniques. We are also investigating the modification of conduction properties by pharmacologically altering ion channel characteristics, an approach that has led to clinical studies in multiple sclerosis and spinal cord injury.

In addition, we are studying the role of sodium channels in the regulation of excitability of pain-signaling sensory neurons. On the basis of studies of familial erythromelalgia, which provides a genetic model of neuropathic pain in humans, we have identified sodium channel Nav1.7 (encoded by gene SCN9A) as a major player in pain. Our recent paper in JAMA Neurology (Geha et al, 2016) moves us closer to personalized, genomically-guided treatment of patients with pain. The second, published recently in Science Translational Medicine (Cao et al, 2016) reports the first results, in humans, on a new class of pain medications that selectively target peripheral sodium channel Nav1.7, and thus do not have central side-effects.

Both studies were carried out in patients with inherited erythromelalgia (IEM, also known as the “Man-on-Fire” syndrome), a human genetic model of neuropathic pain. Affected individuals experience excruciating burning pain due to gain-of-function mutations in Nav1.7 that make pain-signaling neurons hyperexcitable, so that they send high-frequency pain signals in response to benign triggers such as mild warmth.

Our pharmacogenomic approach, now published in JAMA Neurology, interrogated the genomes of patients with IEM to search for gene variants that enhance responsiveness to existing medications, and used molecular modeling and functional analysis to confirm drug engagement of Nav1.7 for two patients with one particular mutation (S241T). Our double-blind, placebo-controlled study demonstrated that the drug, carbamazepine, reduced the patients’ pain. Functional imaging showed that reduction in pain was paralleled by a shift in brain activity from areas involved in emotional processing to areas encoding accurate sensation. Although these observations apply in the strictest sense only to patients carrying one unique IEM mutation, our results provide proof-of-principle that this precision medicine approach, using genomics and molecular modeling, can match patients with specific medications for relief of chronic pain.

Our second approach uses selective targeting of peripheral sodium channel Nav1.7, based on our validation of Nav1.7 as a human pain target through studies that began in 2004. In a collaboration with Pfizer that began in 2009, we studied a subtype-specific Nav1.7 blocker as a prototype of a new class of orally bioavailable compounds that may achieve pain relief without central side effects. Together with Pfizer, we now report in Science Translational Medicine that blockade of Nav1.7 reduces firing in nociceptive neurons, and provides pain relief in human subjects carrying gain-of-function mutations in Nav1.7. We also demonstrate the use of induced pluripotent stem cells (iPSC) as a patient-derived “pain-in-a-dish” model containing the patient’s entire genome that can enable rapid screening of drugs for pain. With ongoing collaborations with biopharmaceutical companies including Convergence-Biogen, we are optimistic that pain-relief through selective Nav1.7 blockade can be achieved for more common pain indications within the general population.

The Editorial accompanying our pharmacogenomic study in JAMA Neurology noted that “this study provides an intelligent practical demonstration of the growing value of molecular neurological reasoning… There are relatively few examples in medicine where molecular reasoning is rewarded with a comparable degree of success.” There is a lot of work ahead of us, but we are optimistic that our findings presage the arrival of a new generation of precision treatments for patients with chronic pain.

We hope that our work will lead to new therapies not only for neuropathic pain but also for multiple sclerosis, spinal cord injury, and related disorders.

Specialized Terms: Axons; Electrophysiology; Genes; Ion Channels; Molecular Biology; Multiple Sclerosis; Pain Syndromes; Sodium Channels; Spinal Cord Injury; Stroke; Translational Neuroscience.

Education
  • MD, Albert Einstein College, 1972
  • PhD, Albert Einstein College, 1970
Publications
  • Faber, C.G., Lauria, G., Merkies, I.S.J., Cheng, X., Han, C., Ahn, H-S., Persson, A-K., Hoeijmakers, J.G.J., Gerrits, M.M., Pierro, T., Lombardi, R., Kapetis, D., Dib-Hajj, S.D., and Waxman, S.G. Gain-of-function NaV1.8 mutations in painful neuropathy. PNAS, 109:19444-19449, 2012. PMID: 23115331
  • Dib-Hajj, S.D., Yang, Y., Black, J.A., Waxman, S.G. The NaV1.7 sodium channel: from molecule to man. Nat Rev Neurosci, 14(1): 49-62, 2012. PMID: 23232607
  • Yang, Y., Dib-Hajj, S.D., Zhang, J., Zhang, Y., Tyrrell, L., Estacion, M., and Waxman, S.G. Structural modeling and mutant cycle analysis predict pharmacoresponsiveness of a NaV1.7 mutant channel, Nature Comm., 3: 1186, 2012. PMID 23149731
  • Waxman, S.G. (2008) Sodium Channels and neuroprotection in MS: current status., Nature Clinical Neurology, 4, 159-170
  • Black, J.A., Nikolajsen, L., Kroner, K., Jensen, T.S., and Waxman, S.G., Multiple sodium channel isoforms and MAP kinases are present in painful human neuromas. Annals of Neurology, 64(6): 644-53, 2008. PMID: 19107992.
  • Rush, A.M., Cummins, T.R., Waxman, S.G. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J. Physiol. 579:1-14, 2007. PMID: 17158175
  • Waxman, S.G., Channel, neuronal, and clinical function in sodium channelopathies: From genotype to phenotype. Nature Neuroscience, 10:405-410, 2007. PMID: 17387329
  • Waxman, S.G. Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nature Rev. Neurosci., 5: 932-942, 2006. PMID: 17115075
  • Geha, P., Yang, Y., Estacion, M., Schulman, B.R., Tokuno, H., Apkarian, A.V., Dib-Hajj, S.D., Waxman, S.G. Pharmacotherapy for pain in a family with inherited erythromelalgia guided by genomic analysis and functional profiling. JAMA Neurol., in press, 2016. PMID: 27088781
  • Cao, L., Nitzsche, N., McDonnell, A., Alexandrou, A., Saintot, P-P., Loucif, A.J.C., Brown, A.R., Young, G., Mis, M., Randall, A., Waxman, S.G., Stanley, P., Kirby, S., Tarabar, S., Gutteridge, A., Butt, R., McKernan, R.M., Whiting, R., Ali, Z., Bilsland, J., Stevens, E.B. Pharmacological reversal of pain phenotype in iPSC-derived sensory neurons and human subjects with inherited erythromelalgia, Science Translational Medicine, 8(335): 335ra56, 2016. PMID: 27099175
International activities
  • PROPANE Neuropathy Genomics Project
    Italy (2012-Present)
    We are the molecular neurobiology/functional genomics arm of an international project, funded by the EU, examining the genetic basis and molecular pathophysiology of painful peripheral neuropathies.

  • CRS Injury and Repair
    London, United Kingdom (2008-Present)
    International Health Yale School of Medicine Yale-London collaboration in CNS injury and repair. This is a formal collaboration established by Dr. Waxman involving research on injured nervous system which takes the form of an exchange of trainees and faculty.

    University College London, University College London

  • International Pain Genomics Consortium
    Netherlands (2008-Present)
    Our laboratory is the hub for studies on rare families, from throughout the world, with mutations of ion channels that produce a pain phenotype. We have major collaborations with University of Radboud, Netherlands; University of Maastrich, Netherlands; and Beijing University

  • Editor, Journal of Physiology
    United Kingdom (2005-2012)
    Editor, Journal of Physiology

  • Visiting Professor of Anatomy, Biology, and Clinical Neurology, University College London
    (1998-Present)
    Visiting Professor of Anatomy, Biology, and Clinical Neurology, University College London

Current projects

My laboratory focuses on functional recovery in diseases of the brain and spinal cord. In particular, we use a spectrum of methods including molecular biology and genetics, cell biology, electrophysiology, computer simulations, molecular modeling etc. to understand how the nervous system responds to injury, and how we can induce functional recovery. Approaching these issues from a molecule- and mechanism-driven standpoint, we have a special interest in spinal cord injury, multiple sclerosis, and neuropathic pain. Our early studies demonstrated the molecular basis for remissions in MS. We have a major interest in the role of ion channels in diseases of the brain and spinal cord. We have demonstrated, for example, that following injury to their axons, spinal sensory neurons turn off some sodium channel genes, while turning others on. This results in the production of different types of sodium channels (with different kinetics and voltage-dependencies) in these neurons, causing them to become hyperexcitability and thereby contributing to neuropathic pain.

We are also interested in hereditary neuropathic pain and have delineated, for the first time, the molecular basis for a hereditary pain syndrome (inherited erythromelalgia; OMIM #133020;#603415). We have identified mutations in ion channel genes that cause painful peripheral neuropathy, and are moving toward pharmacogenomically-guided pain pharmacotherapy.

My laboratory is also examining the role of abnormal sodium channel expression in spinal cord injury (SCI) and multiple sclerosis (MS). Specific projects focus on molecular mechanisms of recovery of conduction along demyelinated axons, and on molecular substrates of axonal degeneration. We are also studying neuroprotection, and have demonstrated that it is possible to pharmacologically protect axons, so they don't degenerate in SCI and MS.

Honors
  • Magnuson Award for Outstanding Achievements in Rehabilitation Research
  • W.I. McDonald Award, British Multiple Sclerosis Society
  • William S Middleton Award (highest scientific honor of the Dept of Veterans Affairs, presented at Ceremonies at the U.S. Capitol).
  • Annual Review Prize, The Physiological Society (Premier Award of the Society previous awardees include J.C. Eccles, A.F. Huxley, A.L. Hodgkin)
  • Honorary Member, Association of British Neurologists
  • Reingold Award, National Multiple Sclerosis Society
  • Dystel Prize for Research on Multiple Sclerosis, awarded jointly by the American Academy of Neurology and the Natl MS Society
  • Wartenberg Award, American Academy of Neurology
  • Honorary Senior Fellow, Institute of Neurology, London
  • Elected to Institute of Medicine, National Academy of Sciences
  • Listed in The Best Doctors in America
  • Member, Dana Alliance for Brain Initiatives
  • Distinguished Alumnus Award, Albert Einstein College of Medicine
  • Fellow, Royal Society of Medicine
  • Established Investigator, National Multiple Sclerosis Society
  • Research Career Development Award, NINCDS
  • Trygve Tuve Memorial Award for Outstanding Contributions in the Biomedical Sciences, NIH