Stephen Waxman
American neurologist and neuroscientist
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Early life and education
Stephen Waxman was born on August 17, 1945, and grew up in Newark, New Jersey. His father was a court reporter and his mother a housewife. Waxman received his BA from Harvard University (1967), and his PhD (1970) and MD (1972) degrees from Albert Einstein College of Medicine. After finishing medical and graduate school, Waxman trained as a Postdoctoral Fellow at MIT, a Clinical Fellow at Harvard Medical School, and a Resident at Boston City Hospital until 1975. He then served on the faculty at Harvard Medical School and MIT prior to being recruited in 1978, at age 33, as Professor of Neurology at Stanford University Medical School and Chief of Neurology at the Palo Alto Veterans Administration Hospital.
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Research
Stephen Waxman became interested in nerve fibers, and how they carry messages from one nerve cell to the next in the form of nerve impulses, as a student doing research at Harvard and University College London in the 1960s. At that time, it was widely assumed that nerve fibers had evolved so as to transmit nerve impulses from one end to the other as rapidly as possible. Waxman showed that in some parts of the nervous system, nerve fibers function differently and act as “delay lines”, carrying information at less-than-maximal velocity. This occurs, for example, in motor systems where timing is critical and the moment of arrival of each nerve impulse must be finely tuned to within thousandths of a second. This early work, and related studies in which Waxman demonstrated that nerve fibers can act as filters, transforming and processing some messages rather than merely transmitting them, established Waxman as a leading figure in neuroscience research. One of Waxman's first papers appeared in Nature while he was still a medical student.
Following medical school, a Ph.D. degree, internship and residency in neurology, Waxman turned his focus to nerve injury and to multiple sclerosis and spinal cord injury, the most common neurologic cripplers of young adults. Waxman became interested in how remissions – recovery of previously lost functions such as vision or the ability to walk – occur in patients with MS. It had been appreciated for nearly a century that in MS, there is damage to the myelin sheath, which wraps around axons and insulates them, and it was assumed that the loss of myelin insulation was the cause of impaired nerve impulse conduction in MS. Waxman showed, however, that the story is much more complicated. In this work, carried out in the mid-1970s, he focused on sodium channels, a family of specialized protein molecules that he likened to “molecular batteries” which produce nerve impulses, and he showed that they were not sprinkled uniformly along the entire length of nerve fibers but, rather, are concentrated at small gaps in the myelin. This implied that parts of the axon lacking sodium channels are uncovered following damage to the myelin, helping to explain why nerve fibers in MS are unable to generate nerve impulses. He then showed that demyelinated nerve fibers recover the capability to transmit nerve impulses by a remarkable “molecular remodeling” in which they acquire additional sodium channels in regions where myelin has been lost. For this work Dr. Waxman was awarded the Dystel Prize, given jointly by the American Academy of Neurology and the National Multiple Sclerosis Society.
Building on his interest in nerve injury and his expertise on sodium channels, Waxman made a series of important discoveries about pain after injury to the nervous system. He was the first to show that after nerve injury, the damaged nerve cells send erroneous pain signals to the brain because they turn on the genes for the wrong types of sodium channels, a phenomenon that Waxman likened to “putting type D batteries into a portable radio that needs AA batteries”. These studies provided a major clue to understanding neuropathic pain.
Waxman's next major studies – carried out at a time when the opiate epidemic was causing deaths around the country – helped to propel the search for new, non-addictive pain medications. Every person who has gone to the dentist knows that, after local injection of a medication like novocain, there is no pain. Novocain, and drugs like it, act by blocking the activity of sodium channels, thus preventing nerve fibers from firing. However, these drugs can not be given systemically via a pill that is swallowed to treat pain, because when the drug reaches the heart and brain, sodium channels in those organs are blocked, so that there is double-vision, impaired balance, sleepiness or confusion. This was a time of rapid new discovery that Waxman called the “molecular revolution”. Discovery that there were multiple types of sodium channels encoded by different genes, each with slightly different properties and a different distribution in the body, triggered the critical question “might there be ‘peripheral sodium channels’, essential for pain-signaling in peripheral nerve cells but not in brain and heart?” and the suggestion that, if these channels existed, it might be possible to selectively block them to alleviate pain without side effects on the heart or brain. Waxman's work contributed to demonstration that three peripheral sodium channels – Nav1.7, Nav1.8, and Nav1.9 – played major roles in pain signaling by peripheral neurons, and demonstrated that all three are major players in pain.
As part of his push to understand these peripheral channels and the genes encoding them – which he came to call “pain genes” – Waxman pursued the goal of “genetic validation”. Here, he reasoned that hereditary pain syndromes, while very rare, could point to key pain-related genes and teach important lessons about the molecular basis for pain. This was the strategy that had enabled the development of statin medications a decade before, when very rare families with inherited hypercholesterolemia pointed the way toward the roles of lipids in heart disease. In 2004-5, in a keystone leap from laboratory to humans, Waxman combined molecular genetics, molecular biology, and biophysics to demonstrate that the Nav1.7 channel is a master regulator of human pain. In these studies Waxman showed that inherited erythromelalgia, also known as the “man on fire syndrome”, is caused by mutations which cause the Nav1.7 sodium channel to turn on inappropriately, thereby producing pain signals that are transmitted to the brain even in the absence of a painful stimulus. This discovery was followed by the demonstration, again by Waxman and his team, that abnormal accumulations of Nav1.7 and Nav1.8 which function in tandem to produce nerve impulses, lead to inappropriate firing of damaged nerves that causes pain in humans after nerve injury and traumatic limb amputation. In collaboration with colleagues at University of Maastricht, Waxman then showed that mutations of Nav1.7 and Nav1.8 can cause relatively common painful peripheral neuropathies. These studies were among the first to show the contribution of sodium channels to human pain.
Waxman was particularly proud of a study in which he used atomic-level modeling to advance pharmacogenomics in a paper that was accompanied by an editorial stating “there are still relatively few examples in medicine where molecular reasoning has been rewarded with a comparable degree of success”. He used computer modeling to assess the ways that different ion channels collaborate like members of a symphony to modulate the messaging of pain-signaling neurons. Waxman also studied why some individuals seem to tolerate pain better than others. Using human stem cells to model painful disease, Waxman pinpointed several “pain resilience” genes. Waxman's studies propelled a generation of clinical studies on a new class of medications aimed at relieving pain by blocking Nav1.7 and Nav1.8.
Awards and distinctions
Waxman has been the recipient of many distinctions:
- 1973 - Trygve Tuve Memorial Award for Outstanding Contributions in the Biomedical Sciences, NIH
- 1975 - Research Career Development Award, NINCDS
- 1987 - Established Investigator, National Multiple Sclerosis Society
- 1991 - Distinguished Alumnus Award, Albert Einstein College of Medicine
- 1991 - Fellow, Royal Society of Medicine
- 1993 - Member, Dana Alliance for Brain Initiatives
- 1994 - Listed in The Best Doctors in America.
- 1995 - The Adrian Lecture (Xth International Congress of Clinical Neurophysiology)
- 1996 - Elected to Institute of Medicine, National Academy of Sciences
- 1999 - Landmark Award for Biomedical Research
- 1999 - Wartenberg Award, American Academy of Neurology
- 1999 - Honorary Senior Fellow, Institute of Neurology, London
- 2000 - Dystel Prize for Research on Multiple Sclerosis, American Academy of Neurology/NMSS
- 2004 - Reingold Award, National Multiple Sclerosis Society
- 2005 - Honorary Member, Association of British Neurologists
- 2009 - W.I. McDonald Award, British Multiple Sclerosis Society
- 2009 - William S Middleton Award (highest scientific honor of the Department of Veterans Affairs, presented at Ceremonies at the U.S. Capitol).
- 2009 - Annual Review Prize, The Physiological Society (Premier Award of the Society; previous awardees include A.F. Huxley, A.L. Hodgkin)
- 2013 - Paul B. Magnuson Award for Outstanding Achievement in Rehabilitation Research, U.S. Department of Veterans Affairs
- 2013 - American Neurological Assoc/Annals of Neurology Prize for Distinguished Contribution to Clinical Neuroscience
- 2014 - Soriano Award, American Neurological Association
- 2018 - Julius Axelrod Prize, Society for Neuroscience