Chasing men on fire: the story of the search for a pain gene

320 Pages·2018·17.067 MB·English

by  Waxman, Stephen G

CHASING MEN ON FIRE

CHASING MEN ON FIRE
The Story of the Search for a Pain Gene
Stephen G. Waxman
The MIT Press
Cambridge, Massachusetts
London, England
© 2018 Massachusetts Institute of Technology
All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means (including
photocopying, recording, or information storage and retrieval) without permission in writing from the publisher.
This book was set in Helvetica LT Std and Times New Roman by Toppan Best-set Premedia Limited. Printed and bound
in the United States of America.
Library of Congress Cataloging-in-Publication Data is available.
Names: Waxman, Stephen G., author.
Title: Chasing men on fire : the story of the search for a pain
gene / Stephen G. Waxman ; foreword by James E. Rothman.
Description: Cambridge, MA : The MIT Press, [2018] | Includes bibliographical
references and index.
Identifiers: LCCN 2017026622 | ISBN 9780262037402 (hardcover : alk. paper)
Subjects: | MESH: Pain--genetics | Pain Management | NAV1.7 Voltage-Gated
Sodium Channel
Classification: LCC RB127 | NLM WL 704 | DDC 616/.0472--dc23 LC record available at https://lccn.loc.gov/2017026622
10 9 8 7 6 5 4 3 2 1
For P, G, and those who shared their DNA.
And for M, W, RT, and JD; for D, J, CJ, and L; and of course for M…

CONTENTS
Foreword by James E. Rothman ix
Preface xi
Acknowledgments xiii
PART I DISSECTING GOD’S MEGAPHONE 1
1 Dissecting God’s Megaphone: The Search for a Pain Gene 3
2 Sherrington’s Enchanted Loom and Huxley’s Science Fiction 9
PART II CHASING MEN ON FIRE: THE SEARCH 23
3 Alabama to Beijing … and Back 25
Cummins et al.: Electrophysiological Properties of Mutant Na 1.7 Sodium Channels in a
V
Painful Inherited Neuropathy 35
Dib-Hajj et al.: Gain-of-Function Mutation in Na 1.7 in Familial Erythromelalgia Induces
V
Bursting of Sensory Neurons 45
4 Avalanche 57
Dib-Hajj et al.: The Na 1.7 Sodium Channel: From Molecule to Man 61
V
5 Two Sides of One Coin 85
Rush et al.: A Single Sodium Channel Mutation Produces Hyper- or Hypoexcitability in
Different Types of Neurons 89
6 Eavesdropping 103
Vasylyev et al.: Dynamic-Clamp Analysis of Wild-Type Human Na 1.7 and Erythromelalgia
V
Mutant Channel L858H 109
PART III BEYOND THE SEARCH: EXPANDING HORIZONS 133
7 Twisted Nerve: A Ganglion Gone Awry 135
Black et al.: Multiple Sodium Channel Isoforms and Mitogen-Activated Protein Kinases
Are Present in Painful Human Neuromas 139
8 Crossing Borders 155
9 From Zebras to Horses 163
Faber et al.: Gain of Function Na 1.7 Mutations in Idiopathic Small Fiber
V
Neuropathy 175
Persson et al.: Neuropathy-Associated Na 1.7 Variant I228M Impairs Integrity of Dorsal
V
Root Ganglion Neuron Axons 195
viii Contents
10 Ripples 205
PART IV MUTING GOD’S MEGAPHONE: FROM THE SQUID TOWARD THE CLINIC 213
11 Seven Years from Theory toward Therapy … via “Pain in a Dish” 215
Cao et al.: Pharmacological Reversal of a Pain Phenotype in iPSC-Derived Sensory
Neurons and Patients with Inherited Erythromelalgia 225
12 From Trial-and-Error to First-Time-Around: Toward Genomically Guided
Therapy 247
Yang et al.: Structural Modelling and Mutant Cycle Analysis Predict
Pharmacoresponsiveness of a Na 1.7 Mutant Channel 251
V
13 Precision 271
Geha et al.: Pharmacotherapy for Pain in a Family with Inherited Erythromelalgia Guided
by Genomic Analysis and Functional Profiling 275
14 “The Important Thing Is Not to Stop” 289
Glossary 293
Index 297