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 decades-long path of discovery offers important lessons concerning how important progress in medicine is achieved: taking a risk in tackling a seemingly insurmountable problem, staying the course, following the scientific method with rigor and enthusiasm.
I have had the opportunity of following the bookends of the story close up, first as Steve Waxman’s colleague at Stanford Medical School in the late 1970s, near the beginning, and now at Yale School of Medicine. Waxman, trained both as a neurologist and a molecular neuroscientist, begins by noting, “Two soldiers may both have missile wounds injuring the same nerve. One is disabled by neuropathic pain, unable to touch the injured limb because feather-light contact triggers immense discomfort, while the other notices numbness but no pain at all.” And he then poses the question, “Might the difference lie in their genes?”
Genes can teach us much about human health and disease. One way to pinpoint critically important genes is to locate and study families in which an experiment of nature—a mutated gene—causes inherited disease. This approach has famously led to the discovery of genes influencing many diseases ranging from cystic fibrosis in children to Alzheimer’s disease in the aging. Waxman has followed this path in a worldwide search—a hunt that spanned forty years and thousands of miles—for families with inherited pain. Within these very unusual families there was a secret, a gene that encodes a master switch that can turn pain on or off.
Interestingly, the story is told via two intertwined narratives. The scientific narrative is relayed by a series of research papers intended for professional scientists that illustrate the steps forward in the search for a pain gene. These papers provide an excellent example of “bench to bedside” research that, in this case, reaches from genes, to molecules that enable neurons to signal each other, then to pain-signaling nerve cells that shriek when they should be whispering, and finally to people who feel they are on fire, people suffering from excruciating pain due to alterations in a single gene. These “people on fire” provide a genetic model of neuropathic pain.
Happily for the nonspecialist, the primary research papers are accompanied by commentaries that explain what the research means, why it needed to be done, and how it was done. Here we get a rare glimpse, provided by a working scientist, into how scientific collaborations arise, how discoveries are made, how a finding on one disease can inform research on other disorders, and how research is “translated” from the laboratory bench to the clinic. These personal accounts tell a story of “how science happens.”
The identification of a pain gene may be relevant to many of us. Following up on the identification of one specific gene as a central player in the man on fire syndrome, research on that gene has extended to the broader general population, where it is important in common disorders such as trigeminal neuralgia that can affect any of us. Research on this gene also provides a vivid example of the developing strategy of precision medicine, guided by genomics, that has the promise of relieving pain “first time around.” It may also point the way toward development of a new class of pain medications that are more effective and that do not have addictive potential. While much remains to be accomplished before the scourge of chronic pain can be effectively treated in most people, we now have a strong scientific foundation that in the fullness of time will enable this, thanks in significant part to the passionate and effective contributions chronicled here.
James E. Rothman
Nobel Laureate in Physiology or Medicine (2013)
Professor, Yale University