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 scientists-in-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.
Chronic pain affects more than 250 million sufferers around the world, is a leading cause of disability, and occurs more frequently than cancer, heart disease, and diabetes combined. The available pain medications are often ineffective or only partially effective. The number of patients needed to be treated, in order to achieve a 50% reduction in pain, is more than four for most of the currently available medications. And, many of the currently available pain medications produce side effects that impair quality of life and limit their use. There is a pressing need for new and better pain medications, and that, in turn, requires that we understand pain at a fundamental level.
The cells within our bodies, including pain-signaling nerve cells, are built largely of protein molecules. The blueprints for these essential building blocks are contained within the human genome, within more than 20,000 genes. Thus genes can tell us how pain-signaling nerve cells work, and might show us how to design new medications.
This type of genetic approach propelled the development of the statin medications, which regulate our lipid levels and have had an immense impact on health. In the case of the statins, it was the discovery and study of very rare families with inherited hypercholesterolemia that pointed the way to drugable molecular targets and ultimately to a new class of medicines. Rare genetic disorders can teach us important lessons about more common diseases. By analogy to the statins, the discovery of a “pain gene” would almost certainly teach us important lessons about chronic pain and how it arises. It also might facilitate the development of more effective pain medications, hopefully devoid of “central” side effects such as confusion, loss of balance, sleepiness, and addictive potential.
This book provides a personal account of the search for a pain gene. By a “pain gene” I mean a gene that encodes protein molecules that are central players in pain, and that, when gone mutant in very rare families, causes severe pain or, conversely, inability to sense pain. The search was propelled by these questions: “Why does one soldier with a nerve injury experience incapacitating pain, while another soldier with a similar injury does not? Why does one person with diabetic neuropathy suffer from debilitating burning pain, while another person with diabetic neuropathy notices numbness and tingling without significant discomfort? And, most importantly, can we develop new therapeutic strategies that might help those who suffer from chronic pain?”
The chapters in this book tell two intertwined stories. The scientific story is told by eleven primary papers documenting steps forward in the search for a pain gene and in the quest to cure pain. These papers are accompanied by personal accounts that explain what the research means, why it needed to be done, and how it was done. These commentaries tell the story behind the science—a story of “how science happens.”
There are four sections to this book. The chapters in the first section, “Dissecting God’s Megaphone,” set the stage. Within the second section, “Chasing Men on Fire: The Search,” the first two chapters trace the path to discovery of the pain gene. The following two chapters describe the beauty and intricacy of the channel encoded by the pain gene; these chapters will be of interest to readers with a passion for detail, although others may choose to skip them. The third section of this book, “Beyond the Search: Expanding Horizons,” shows how the search for a pain gene in a rare disease has informed research on more common disorders. And the final section, “Muting God’s Megaphone: From the Squid toward the Clinic,” shows how discovery of the pain gene is being used to develop new treatments for pain.
Scientific papers are often filled with jargon. I have tried, wherever possible, to avoid jargon in the commentaries that accompany the primary papers in this book. Nevertheless, a few words of explanation are in order: A focus of this book is a rare medical disorder called erythromelalgia, which has also been termed erythermalgia in the medical literature and the “man on fire” syndrome in the lay literature. Since it is quite rare, only a minority of physicians have seen patients with erythromelalgia. But once they have seen a patient, the physician remembers this rare disorder because the clinical picture is striking: People with erythromelalgia—even in the absence of a hot stimulus—suffer from intense burning pain. They describe the pain as a sensation of being scalded, or having their body filled with hot lava. Men and women with the inherited form of erythromelalgia—a subset of about 5% of individuals with erythromelalgia, in whom there is a genetic cause—pointed the way to the pain gene.
Throughout this book, I refer to “DRG neurons.” This term refers to dorsal root ganglion neurons. These are the primary sensory neurons, with cell bodies located in clusters outside the spinal cord, that innervate our body surface and organs. DRG neurons play a central role in inherited erythromelalgia and in other pain disorders and are the cells where NaV1.7, a molecule essential for the sensation of pain, is highly expressed.
The identification of a pain gene is especially timely now. In the wake of identification of one specific gene as a major player in the man on fire syndrome, research on that gene has extended from rare genetic disorders to the general population, where it is important in common disorders that can affect all of us. Research on this gene may pave the way for pharmacogenomics, which will transform pain management from trial and error to “first time around.” It may also point the way toward development of novel, more effective pain medications.
As important as a pain gene was, it was not easy to find. Neurologists see chronic pain frequently in clinical practice, but most neurologists have never encountered, and never will encounter, families with genetic pain disorders. The search for a pain gene spanned thousands of miles, from New Haven to Alabama to Beijing and then to the Netherlands. It required the coordinated efforts of geneticists, neurophysiologists, pharmacologists, molecular and cell biologists, as well as clinicians, and it was facilitated by collaborations of researchers on three continents. It was also propelled by the patients themselves, by the DNA that they shared with researchers and by the personal accounts they provided of their pain. The story behind the search reaches from genes, to the protein molecules they produce, to pain-signaling neurons that scream when they should be silent, and then to actual people—people who feel they are on fire. And the story points the way to molecules that produce pain not only in the man on fire syndrome, but also more broadly in “the rest of us” within the general population.
This book tells that story.