Chasing Men on Fire: The Story of the Search for a Pain Gene (The MIT Press)

"Two soldiers, both with wounds injuring the same nerve, show very different responses: one is disabled by neuropathic pain, unable to touch the injured limb because even the lightest contact triggers excruciating discomfort; the other notices numbness but no pain at all. Could the difference lie in their genes? In this book, described in the foreword by Nobel Laureate James Rothman as so well written that it reads like a detective novel, Stephen Waxman recounts the search for a gene that controls pain -- a search spanning more than thirty years and three continents. The story moves from genes to pain-signaling neurons that scream when they should be silent to people with a rare genetic disorder who feel they are on fire. Waxman explains that if pain-signaling neurons are injured by trauma or disease, they can become hyperactive and send pain signals to the brain even without external stimulus. Studying the hyperactive mutant pain gene in man on fire syndrome has pointed the way to molecules that produce pain more broadly within the general population, in the rest of us. Waxman's account of the many steps that led to discovery of the pain gene tells the story behind the science, of how science happens."--Publisher description.;Dissecting God's megaphone : the search for a pain gene -- Sherrington's enchanted loom and Huxley's science fiction -- Alabama to Beijing and back -- Avalanche -- Two sides of one coin -- Eavesdropping -- Twisted nerve : a ganglion gone awry -- Crossing borders -- From zebras to horses -- Ripples -- Seven years from theory toward therapy via "pain in a dish" -- From trial-and-error to first-time-around : toward genomically-guided therapy -- Precision -- "The important thing is not to stop." CONTENTS 9 FOREWORD 11 PREFACE 13 ACKNOWLEDGMENTS 15 I DISSECTING GOD’S MEGAPHONE 17 1 DISSECTING GOD’S MEGAPHONE: THE SEARCH FOR A PAIN GENE 19 References 23 2 SHERRINGTON’S ENCHANTED LOOM AND HUXLEY’S SCIENCE FICTION 25 Axons 26 A Morse Code in the Brain 26 Sodium Channels: Molecular Batteries in Our Nerve Cells 27 Dorsal Root Ganglion (DRG) Neurons as Generators of Pain 30 Peripheral Sodium Channels—A Holy Grail 32 References 36 II CHASING MEN ON FIRE: THE SEARCH 39 3 ALABAMA TO BEIJING ... AND BACK 41 References 49 ELECTROPHYSIOLOGICAL PROPERTIES OF MUTANT NaV1.7 SODIUM CHANNELS IN A PAINFUL INHERITED NEUROPATHY 51 Introduction 51 Materials and Methods 52 Results 52 Discussion 55 Acknowledgments 58 About the Authors 58 References 58 GAIN-OF-FUNCTION MUTATION IN NaV1.7 IN FAMILIAL ERYTHROMELALGIA INDUCES BURSTING OF SENSORY NEURONS 61 Introduction 61 Subjects and Methods 61 Results 62 Discussion 67 Acknowledgments 69 About the Authors 70 References 70 4 AVALANCHE 73 References 75 THE NaV1.7 SODIUM CHANNEL: FROM MOLECULE TO MAN 77 Cellular and Subcellular Distribution 79 Biophysical Properties 79 Roles in Multiple Sensory Modalities 81 Putative Role in Epilepsy 82 Roles in Pain States 82 Structural Features of NaV1.7 88 Dependence on Neuronal Background 90 Targeting NaV1.7 for Pain Treatment 91 Summary and Future Directions 93 Acknowledgments 93 About the Authors 94 Competing Interests Statement 94 Databases 94 Further Information 94 Glossary 94 Notes 94 5 TWO SIDES OF ONE COIN 101 References 104 A SINGLE SODIUM CHANNEL MUTATION PRODUCES HYPEROR HYPOEXCITABILITY IN DIFFERENT TYPES OF NEURONS 105 Results 106 Discussion 112 Materials and Methods 114 Acknowledgments 116 About the Authors 116 Notes 116 6 EAVESDROPPING 119 References 122 DYNAMIC-CLAMP ANALYSIS OF WILD-TYPE HUMAN NaV1.7 AND ERYTHROMELALGIA MUTANT CHANNEL L858H 125 Materials and Methods 126 Results 128 Discussion 142 Grants 145 About the Authors 146 Disclosures 146 Author Contributions 146 References 146 III BEYOND THE SEARCH: EXPANDING HORIZONS 149 7 TWISTED NERVE: A GANGLION GONE AWRY 151 Note 153 References 154 MULTIPLE SODIUM CHANNEL ISOFORMS AND MITOGEN-ACTIVATED PROTEIN KINASES ARE PRESENT IN PAINFUL HUMAN NEUROMAS 155 Patients and Methods 156 Results 158 Discussion 163 Acknowledgments 166 About the Authors 166 References 167 8 CROSSING BORDERS 171 Woods Hole 172 The War Room 172 Beijing 173 Nijmegen 174 Maastricht 175 References 177 9 FROM ZEBRAS TO HORSES 179 References 188 GAIN OF FUNCTION NaV1.7 MUTATIONS IN IDIOPATHIC SMALL FIBER NEUROPATHY 191 Patients and Methods 192 Results 194 Discussion 204 Acknowledgments 207 About the Authors 207 Authorship 207 Potential Conflicts of Interest 208 References 208 NEUROPATHY-ASSOCIATED NaV1.7 VARIANT I228M IMPAIRS INTEGRITY OF DORSAL ROOT GANGLION NEURON AXONS 211 Materials and Methods 212 Results 212 Discussion 216 Acknowledgments 218 About the Authors 218 Potential Conflicts of Interest 218 References 218 10 RIPPLES 221 References 226 IV MUTING GOD’S MEGAPHONE: FROM THE SQUID TOWARD THE CLINIC 229 11 SEVEN YEARS FROM THEORY TOWARD THERAPY ... VIA “PAIN IN A DISH” 231 New Medicines: A Big Challenge 231 From Theory toward Therapy 233 Enabler 234 Disease in a Dish 236 Waiting While Blinded 237 References 239 PHARMACOLOGICAL REVERSAL OF A PAIN PHENOTYPE IN iPSC-DERIVED SENSORY NEURONS AND PATIENTS WITH INHERITED ERYTHROMELALGIA 241 Introduction 241 Results 242 Discussion 249 Materials and Methods 254 Supplementary Materials 258 Acknowledgments 258 About the Authors 258 Funding 259 Author Contributions 259 Competing Interests 259 Data and Materials Availability 259 References and Notes 260 12 FROM TRIAL-AND-ERROR TO FIRST-TIME-AROUND: TOWARD GENOMICALLY GUIDED THERAPY 263 From Bacteria to Humans 264 Modeling Molecules to Predict Drug Actions 265 References 266 STRUCTURAL MODELLING AND MUTANT CYCLE ANALYSIS PREDICT PHARMACORESPONSIVENESS OF A NaV1.7 MUTANT CHANNEL 267 Results 268 Discussion 276 Methods 281 Acknowledgments 283 About the Authors 283 Author Contributions 284 Additional Information 284 References 284 13 PRECISION 287 References 290 PHARMACOTHERAPY FOR PAIN IN A FAMILY WITH INHERITED ERYTHROMELALGIA GUIDED BY GENOMIC ANALYSIS AND FUNCTIONAL PROFILING 291 Methods 292 Results 294 Discussion 300 Conclusions 302 Acknowledgments 302 About the Authors 302 References 303 14 “THE IMPORTANT THING IS NOT TO STOP” 305 References 307 GLOSSARY 309 INDEX 313 A thirty-year quest, from genes to pain-signaling neurons to people with a rare genetic disorder that makes them feel they are on fire.Two soldiers, both with wounds injuring the same nerve, show very different responses: one is disabled by neuropathic pain, unable to touch the injured limb because even the lightest contact triggers excruciating discomfort; the other notices numbness but no pain at all. Could the difference lie in their genes? In this book, described in the foreword by Nobel Laureate James Rothman as “so well written that it reads like a detective novel,” Stephen Waxman recounts the search for a gene that controls pain—a search spanning more than thirty years and three continents. The story moves from genes to pain-signaling neurons that scream when they should be silent to people with a rare genetic disorder who feel they are on fire. Waxman explains that if pain-signaling neurons are injured by trauma or disease, they can become hyperactive and send pain signals to the brain even without external stimulus. Studying the hyperactive mutant pain gene in man on fire syndrome has pointed the way to molecules that produce pain more broadly within the general population, in the rest of us. Waxman's account of the many steps that led to discovery of the pain gene tells the story behind the science, of how science happens. A thirty-year quest, from genes to pain-signaling neurons to people with a rare genetic disorder that makes them feel they are on fire. Two soldiers, both with wounds injuring the same nerve, show very different one is disabled by neuropathic pain, unable to touch the injured limb because even the lightest contact triggers excruciating discomfort; the other notices numbness but no pain at all. Could the difference lie in their genes? In this book, described in the foreword by Nobel Laureate James Rothman as so well written that it reads like a detective novel, Stephen Waxman recounts the search for a gene that controls paina search spanning more than thirty years and three continents. The story moves from genes to pain-signaling neurons that scream when they should be silent to people with a rare genetic disorder who feel they are on fire. Waxman explains that if pain-signaling neurons are injured by trauma or disease, they can become hyperactive and send pain signals to the brain even without external stimulus. Studying the hyperactive mutant pain gene in man on fire syndrome has pointed the way to molecules that produce pain more broadly within the general population, in the rest of us. Waxman's account of the many steps that led to discovery of the pain gene tells the story behind the science, of how science happens.