Cover

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Title Page, Copyright, Dedication

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pp. i-vi

CONTENTS

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pp. vii-viii

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FOREWORD

James E. Rothman

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pp. ix-x

If you are interested in how scientific medicine is done, this is cause enough to read this book. Whether you are a layperson or a scientist, if you are interested in the brain and the nervous system, you will also be interested because Waxman explains the ideas and their history so clearly and simply and yet accurately. Indeed the book is so well written that it reads like a detective novel, making it irresistible to turn the next page (or swipe the screen of your Kindle).

The explicit focus is Waxman’s lifelong pursuit as a neurologist of how pain arises, how we can better understand it, and how new medicines for pain can be developed to treat it. He has had remarkable success in this pursuit initially through the discovery of a gene that controls pain. Waxman’s...

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PREFACE

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pp. xi-xii

This volume had its origin when several people suggested that I write a book on my search for a pain gene, a gene that controls pain sensibility in humans. Each suggested that the topic was timely, but each imagined a book for a different audience. A colleague forwarded the idea of a text for scientistsin-training and physicians-in-training, another suggested a book for a lay readership interested in pain, and still another suggested a volume for scientists and physicians. In the end, after consulting with colleagues, book publishers, and editors, and ultimately with Bob Prior of MIT Press, I decided to take a hybrid approach, combining some of my primary papers with commentaries that place them in a broader context in order to reach all these audiences....

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ACKNOWLEDGMENTS

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pp. xiii-xiv

None of us lives or works in a vacuum, and I certainly have not. I owe an immense debt to my teachers and mentors. These have included J. David Robertson and Howard Hermann of Harvard Medical School and J. Z. Young of University College London. My mentors at the Albert Einstein College of Medicine, neurophysiologist Dominick Purpura and electron microscopist George Pappas, showed by example that neuroscience is not constrained by any single set of methods but can, on the contrary, be truly multidisciplinary; Michael Bennett, also a professor at Einstein, provided an example of rigor in electrophysiology and, both at Einstein and during summers at the Marine Biological Laboratory in Woods Hole, pointed my research compass in the direction of axons. As a medical student, I also had...

I DISSECTING GOD’S MEGAPHONE

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1 DISSECTING GOD’S MEGAPHONE: THE SEARCH FOR A PAIN GENE

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pp. 3-8

Each one of us, at some time during our lives, experiences physical pain. Although C. S. Lewis, in his much-cited comment, was referring to spiritual pain, physical pain can also be considered to be God’s megaphone. The sensation of physical pain—“My body hurts!”—is nearly universal. When pain is transient, it can protect us, warning us to withdraw from a threatening situation. Pain can also teach us—most children rapidly learn, for example, not to touch hot objects. But pain is not always helpful. If pain persists after a painful stimulus is no longer there and becomes chronic, it can invade a life and change it....

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2 SHERRINGTON’S ENCHANTED LOOM AND HUXLEY’S SCIENCE FICTION

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pp. 9-22

The human nervous system—our brain, spinal cord, and nerves—is the world’s most complex computer. There are more than 100 billion nerve cells in the human brain and spinal cord, greater than the number of stars within the Milky Way.

These nerve cells, called neurons by scientists, act as tiny transistors, or in some cases as integrated circuits. They send electrical impulses to and fro along nerve fibers, termed “axons” by neuroscientists, as the nervous system makes countless computations each second. In 1942, the pioneering British neuroscientist Charles S. Sherrington referred in his book Man on His Nature to the active brain as...

II CHASING MEN ON FIRE: THE SEARCH

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3 ALABAMA TO BEIJING … AND BACK

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pp. 25-34

The search for the pain gene began in an Alabama neighborhood with a group of men and women carrying groceries, talking with each other, tending to their children, or driving down the street. Ordinary, at first glance. But, many of the people did not wear regular shoes. Some wore open toed sandals. Others preferred not to wear anything on their feet, to walk barefoot on a cool tile floor, or in the cold water that collected in puddles. The children avoided the playground. They sometimes missed school days. And, if you spent time with these people, you might hear a person say, “I’m getting an attack.” Then, the affected person would grimace, their feet turning bright red, as if they had been badly sunburned. If asked, they would say that their feet, and sometimes their hands, felt as if they were on fire....

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ELECTROPHYSIOLOGICAL PROPERTIES OF MUTANT NaV1.7 SODIUM CHANNELS IN A PAINFUL INHERITED NEUROPATHY

Theodore R. Cummins, Sulayman D. Dib-Hajj, and Stephen G. Waxman

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pp. 35-44

Although the physiological basis of erythermalgia, an autosomal dominant painful neuropathy characterized by redness of the skin and intermittent burning sensation of extremities, is not known, two mutations of NaV1.7, a sodium channel that produces a tetrodotoxin-sensitive, fast-inactivating current that is preferentially expressed in dorsal root ganglia (DRG) and sympathetic ganglia neurons, have recently been identified in patients with primary erythermalgia. NaV1.7 is preferentially expressed in small-diameter DRG neurons, most of which are nociceptors, and is characterized by slow recovery from...

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GAIN-OF-FUNCTION MUTATION IN NaV1.7 IN FAMILIAL ERYTHROMELALGIA INDUCES BURSTING OF SENSORY NEURONS

S. D. Dib-Hajj, A. M. Rush, T. R. Cummins, F. M. Hisama, S. Novella, L. Tyrrell, L. Marshall, and S. G. Waxman

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pp. 45-56

Erythromelalgia is an autosomal dominant disorder characterized by burning pain in response to warm stimuli or moderate exercise. We describe a novel mutation in a family with erythromelalgia in SCN9A, the gene that encodes the NaV1.7 sodium channel. NaV1.7 produces threshold currents and is selectively expressed within sensory neurons including nociceptors. We demonstrate that this mutation, which produces a hyperpolarizing shift in activation and a depolarizing shift in steady-state inactivation, lowers thresholds for single action potentials and high frequency firing in dorsal root ganglion neurons. Erythromelalgia is the first inherited pain disorder in...

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4 AVALANCHE

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pp. 57-60

Soon after we published the functional analysis of the first NaV1.7 mutations from patients with erythromelalgia, I was deluged with an avalanche of emails, letters, and telephone calls from around the world. They were from people with chronic pain. Some of these people had erythromelalgia, and some of them had mutations of NaV1.7 that we had not seen before. Here were new clues. But there also were entreaties, requests for help. Especially touching were the enquiries from parents of children in pain. In the beginning, I felt nearly helpless. I was navigating a large, complex sea.

We were looking for rare experiments of nature in which the gene for NaV1.7 had gone awry, with the hope that each new genetic mistake would teach us something new. To do this, we established a...

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THE NaV1.7 SODIUM CHANNEL: FROM MOLECULE TO MAN

Sulayman D. Dib-Hajj, Yang Yang, Joel A. Black, and Stephen G. Waxman

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pp. 61-84

The voltage-gated sodium channel NaV1.7 is preferentially expressed in peripheral somatic and visceral sensory neurons, olfactory sensory neurons and sympathetic ganglion neurons. NaV1.7 accumulates at nerve fibre endings and amplifies small subthreshold depolarizations, poising it to act as a threshold channel that regulates excitability. Genetic and functional studies have added to the evidence that NaV1.7 is a major contributor to pain signalling in humans, and homology modelling based on crystal structures of ion channels suggests an atomic-level structural basis for the altered gating of mutant NaV1.7 that causes...

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5 TWO SIDES OF ONE COIN

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pp. 85-88

A mutation—a change in a single gene—is termed “pathogenic” when it alters the gene product in a way that causes disease. Within the human genome, there are more than 20,000 genes. Each one of the cells within our body contains all of these 20,000 genes. Yet many mutations selectively impact some tissues or cell types, leaving others unaffected. An example is provided by sickle cell anemia. In this hereditary disorder, a mutation of the HBB gene results in production of an abnormal form of β-globin which is a component of hemoglobin, the iron-containing protein that carries oxygen within the blood from the lungs to other tissues throughout the body. Hemoglobin is present only in red blood cells,...

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A SINGLE SODIUM CHANNEL MUTATION PRODUCES HYPEROR HYPOEXCITABILITY IN DIFFERENT TYPES OF NEURONS

Anthony M. Rush, Sulayman D. Dib-Hajj, Shujun Liu, Theodore R. Cummins, Joel A. Black, and Stephen G. Waxman

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pp. 89-102

Disease-producing mutations of ion channels are usually characterized as producing hyperexcitability or hypoexcitability. We show here that a single mutation can produce hyperexcitability in one neuronal cell type and hypoexcitability in another neuronal cell type. We studied the functional effects of a mutation of sodium channel NaV1.7 associated with a neuropathic pain syndrome, erythermalgia, within sensory and sympathetic ganglion neurons, two cell types where NaV1.7 is normally expressed. Although this mutation depolarizes resting membrane potential in both types of neurons, it renders sensory neurons hyperexcitable and sympathetic neurons hypoexcitable. The...

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6 EAVESDROPPING

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pp. 103-108

Imagine trying to eavesdrop on a room full of people by thrusting a microphone, attached to a ramrod the size of telephone pole, through the wall. Although this technique of listening might allow one to hear some noises, the message would not be representative of what normally goes on within that room. Our intrusive microphone would blatantly disrupt any conversation. That is the type of challenge that is faced by neurophysiologists who wish to study the details of the electrical activity within single nerve cells. These cells measure, on average, less than 30 or 40 microns across, and in many cases, have a diameter of less than 20 microns, one-fiftieth of a millimeter and a fraction of the breadth of a human hair. Compounding the challenge, the electrical signals are tiny, ranging from 1/10 of a volt at...

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DYNAMIC-CLAMP ANALYSIS OF WILD-TYPE HUMAN NaV1.7 AND ERYTHROMELALGIA MUTANT CHANNEL L858H

Dmytro V. Vasylyev, Chongyang Han, Peng Zhao, Sulayman Dib-Hajj, and Stephen G. Waxman

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pp. 109-132

The link between sodium channel NaV1.7 and pain has been strengthened by identification of gain-of-function mutations in patients with inherited erythromelalgia (IEM), a genetic model of neuropathic pain in humans. A firm mechanistic link to nociceptor dysfunction has been precluded because assessments of the effect of the mutations on nociceptor function have thus far depended on electrophysiological recordings from dorsal root ganglia (DRG) neurons transfected with wild-type (WT) or mutant NaV1.7 channels, which do not permit accurate calibration of the level of NaV1.7 channel expression. Here, we report an analysis of the function of WT NaV1.7 and IEM L858H ...

III BEYOND THE SEARCH: EXPANDING HORIZONS

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7 TWISTED NERVE: A GANGLION GONE AWRY

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pp. 135-138

The man on fire syndrome is very rare. Neuropathic pain is not. It occurs commonly in disorders as diverse as traumatic limb amputations, nerve or nerve root compression, and peripheral neuropathy due to many causes. The central molecular player in inherited erythromelalgia, NaV1.7, is pivotal in these disorders too.

The eminent nineteenth-century physician Silas Weir Mitchell—one of the founders of the American Neurological Association—holds a place of special interest to military historians because he tended to wounded soldiers on the Civil War battlefields. At that time, amputation of the injured limb was all that was available to treat bullet wounds, and the concept of the ambulance—initially just a wagon to...

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MULTIPLE SODIUM CHANNEL ISOFORMS AND MITOGEN-ACTIVATED PROTEIN KINASES ARE PRESENT IN PAINFUL HUMAN NEUROMAS

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pp. 139-154

Injury to peripheral nerves associated with trauma, amputation, compression, or surgery can lead to the formation of painful neuromas, tangled masses of blind-ending axons, and proliferating connective tissue.1 In humans, these neuromas can be debilitating, causing chronic and severe pain, which is frequently refractory to medical treatment. Axons in both experimental and human neuromas have been shown...

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8 CROSSING BORDERS

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pp. 155-162

Popular legend has it that when Willie Sutton was asked why he robbed banks, he said “Because that’s where the money is.” I have sometimes been asked why I have worked together with researchers in Europe and Asia. Why travel thousands of miles for a collaboration when there are experts next door? The short answer is “Because those are the collaborations that worked.” But that raises the following questions: What is a fruitful collaboration? How can one make it happen?

Scientific collaborations are driven by need or opportunity. My interest in finding pain genes, and my need to find the right patients, arose from watching my father spend the last years of his life sedated by the opiate medications that were used—unsuccessfully—in an attempt to treat the neuropathic pain...

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9 FROM ZEBRAS TO HORSES

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pp. 163-174

A common admonition at rounds on the wards of teaching hospitals is “when you hear hoofbeats, think of horses,” to which the attending physician might add “and don’t limit your thoughts to zebras.” Zebras, in this setting, refer to rare diseases, while horses stand for common disorders. Our demonstration that gain-of-function changes in mutant NaV1.7 channels cause inherited erythromelalgia (Cummins, Dib-Hajj, and Waxman 2004; Dib-Hajj et al. 2005) and, following that, discovery that other gain-of-function mutations of NaV1.7 cause pain in paroxysmal extreme pain disorder (PEPD) (Fertleman et al. 2006), had shown that hyperactivity of NaV1.7 channels can produce disorders characterized by intense pain. But these were very rare diseases, zebras. Might NaV1.7 be a player in chronic pain within broader populations?...

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GAIN OF FUNCTION NaV1.7 MUTATIONS IN IDIOPATHIC SMALL FIBER NEUROPATHY

Catharina G. Faber, Janneke G. J. Hoeijmakers, Hye-Sook Ahn, Xiaoyang Cheng, Chongyang Han, Jin-Sung Choi, Mark Estacion, Giuseppe Lauria, Els K. Vanhoutte, Monique M. Gerrits, Sulayman Dib-Hajj, Joost P. H. Drenth, Stephen G. Waxman, and Ingemar S. J. Merkies

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pp. 175-194

Small nerve fiber neuropathy (SFN) is a relatively common disorder of thinly myelinated and unmyelinated nerve fibers recently recognized as a distinct clinical syndrome.1 The clinical picture is typically dominated by onset in adulthood of neuropathic pain, often with a burning quality, and autonomic symptoms.2–6 The diagnosis of pure SFN, in which small diameter nerve fibers are affected but large diameter fibers are spared, is usually made on the basis of the clinical picture, preservation of large fiber functions (normal strength, tendon reflexes, and vibration sense),...

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NEUROPATHY-ASSOCIATED NaV1.7 VARIANT I228M IMPAIRS INTEGRITY OF DORSAL ROOT GANGLION NEURON AXONS

Anna-Karin Persson, Shujun Liu, Catharina G. Faber, Ingemar S. J. Merkies, Joel A. Black, and Stephen G. Waxman

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pp. 195-204

Small-fiber neuropathy (SFN) is characterized by injury to unmyelinated and thinly myelinated peripheral fibers and loss of intraepidermal nerve fibers (IENF).1–3 IENF are thought to exhibit dynamic plasticity, and although mechanisms underlying IENF depletion in SFN are incompletely understood, available data suggest contributions from both axonal degeneration and reduced axonal regenerative capacity.4

An underlying cause cannot be identified in a substantial proportion of cases of SFN, which are traditionally classified as idiopathic.1–3 Smalldiameter peripheral axons and IENF are known...

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10 RIPPLES

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pp. 205-212

One of the exciting things about science is that it can have an impact beyond what was expected. Research on one project can inform research on another. This can occur because concepts or conclusions, derived from one particular research effort, hold lessons for a second project; or because a new tool or a new method, developed for one project, proves to be useful in a second project; or because expertise accrued for one project turns out be relevant to a second. In some cases this ripple effect can extend from one disease to another. This was the case in the search for a gene in a 15-year-old girl. Analysis of her genes propelled us to use methods from our research on pain to help understand another disorder. Her genes were, in fact, the centerpiece of a touching story....

IV MUTING GOD’S MEGAPHONE: FROM THE SQUID TOWARD THE CLINIC

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11 SEVEN YEARS FROM THEORY TOWARD THERAPY … VIA “PAIN IN A DISH”

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pp. 215-224

Discovering that the SCN9A gene and its NaV1.7 sodium channel play a key role in pain marked, in a sense, a successful end of the search for a pain gene. I could have finished this book at that point. But a larger quest was ahead. Science goes on and on, with the answer to each question raising new challenges and suggesting new possibilities. Turning a target—NaV1.7 in this instance—into a treatment is not easy. There is a lot of work to do in the laboratory before a potential medicine even begins to be tested in humans. Then one must define the appropriate people to test it in, and design the most informative trial. Human subjects with the disease under study have to be located and enrolled. They have to be randomized into multiple groups,...

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PHARMACOLOGICAL REVERSAL OF A PAIN PHENOTYPE IN iPSC-DERIVED SENSORY NEURONS AND PATIENTS WITH INHERITED ERYTHROMELALGIA

Lishuang Cao, Aoibhinn McDonnell, Anja Nitzsche, Aristos Alexandrou, Pierre-Philippe Saintot, Alexandre J.C. Loucif, Adam R. Brown, Gareth Young, Malgorzata Mis, Andrew Randall, Stephen G. Waxman, Philip Stanley, Simon Kirby, Sanela Tarabar, Alex Gutteridge, Richard Butt, Ruth M. McKernan, Paul Whiting, Zahid Ali, James Bilsland, and Edward B. Stevens

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pp. 225-246

In common with other chronic pain conditions, there is an unmet clinical need in the treatment of inherited erythromelalgia (IEM). The SCN9A gene encoding the sodium channel NaV1.7 expressed in the peripheral nervous system plays a critical role in IEM. A gain-of-function mutation in this sodium channel leads to aberrant sensory neuronal activity and extreme pain, particularly in response to heat. Five patients with IEM were treated with a new potent and selective compound that blocked the NaV1.7 sodium channel resulting in a decrease in heat-induced pain in most of the patients. We derived induced pluripotent stem cell (iPSC) lines from four of five subjects and produced sensory neurons that emulated the clinical phenotype of hyperexcitability and aberrant responses to heat stimuli. When we compared the severity of the clinical...

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12 FROM TRIAL-AND-ERROR TO FIRST-TIME-AROUND: TOWARD GENOMICALLY GUIDED THERAPY

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pp. 247-250

Even as NaV1.7 blockers were (and are) being developed, we were also taking another approach: using the human genome to predict whether an existing medication would help a particular person. This approach, variously called “precision medicine,” “personalized medicine,” or “individualized medicine,” uses the DNA of each specific patient to give the clinician a molecular compass that points to the most effective medication. Currently we do not have that molecular compass in pain medicine. The clinician usually begins by selecting a particular medication, based on the patient’s description of the pain, the cause of the pain or its pattern, and other aspects of the patient’s history. The most effective medication, the dosage, and the dosing schedule can vary from patient to patient. The choice of...

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STRUCTURAL MODELLING AND MUTANT CYCLE ANALYSIS PREDICT PHARMACORESPONSIVENESS OF A NaV1.7 MUTANT CHANNEL

Yang Yang, Sulayman D. Dib-Hajj, Jian Zhang, Yang Zhang, Lynda Tyrrell, Mark Estacion, and Stephen G. Waxman

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pp. 251-270

Sodium channel NaV1.7 is critical for human pain signaling. Gain-of-function mutations produce pain syndromes including inherited erythromelalgia, which is usually resistant to pharmacotherapy, but carbamazepine normalizes activation of NaV1.7-V400M mutant channels from a family with carbamazepine-responsive inherited erythromelalgia. Here we show that structural modeling and thermodynamic analysis predict pharmacoresponsiveness of another mutant channel (S241T) that is located 159 amino acids distant from V400M. Structural modeling reveals...

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13 PRECISION

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pp. 271-274

On January 30, 2015, President Barack Obama announced details of the Precision Medicine Initiative (The White House 2015). In launching this initiative, the White House press briefing noted that “most (currently available) medical treatments have been designed for the ‘average patient.’” The announcement went on to describe an “approach to disease prevention and treatment that takes into account individual differences in people’s genes” as well as environment and lifestyle.

Like many colleagues in the scientific community, my team and I at Yale were pleased to learn that this initiative was moving forward. But, as we read the announcement we were bemused, for a very specific reason: As the Precision Medicine Initiative was being discussed by policy makers in...

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PHARMACOTHERAPY FOR PAIN IN A FAMILY WITH INHERITED ERYTHROMELALGIA GUIDED BY GENOMIC ANALYSIS AND FUNCTIONAL PROFILING

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pp. 275-288

Inherited erythromelalgia (IEM) is an autosomal dominant disorder characterized by severe burning pain in the distal extremities, triggered by warmth and relieved by cooling, caused by gain-of-function mutations of the NaV1.7 sodium channel, which is encoded by the SCN9A gene.1 NaV1.7 is preferentially expressed within peripheral sensory dorsal root ganglion (DRG) and sympathetic ganglion neurons,2–4 where it activates at relatively hyperpolarized potentials below the threshold for action potential generation. NaV1.7 amplifies small stimuli, thereby setting the gain for firing.2 In general, the NaV1.7...

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14 “THE IMPORTANT THING IS NOT TO STOP”

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pp. 289-292

When NaV1.7 was identified as a major player in pain and mutations of its SCN9A gene were shown to produce dramatic pain profiles in humans, a pain gene had been found. But science’s arrow never stops flying. Sometimes it advances rapidly, and sometimes slowly. It is now whizzing ahead in laboratory experiments that are teaching us how ion channels work and how their dysfunction can cause disease. And, at the same time, it is slowly inching forward on another track, in studies on novel clinical approaches—small molecule blockers, gene therapy strategies, inhibitors based on modified toxins or antibodies—that will hopefully become new medications that put NaV1.7 to sleep....

GLOSSARY

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pp. 293-296

INDEX

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pp. 297-304