Figure 1.1 Drawing, entitled A Constant Battle, submitted to The Erythromelalgia Association for their 2012 art contest, depicting the pain of erythromelalgia. Reproduced with permission of Jennifer Beech and The Erythromelalgia Association.
God shouts in our pain. It is his megaphone.
—C. S. Lewis
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.
This book tells the story of the search for a gene: a gene controlling pain. It spans forty years and 7,000 miles and describes the discovery of rare families with a fierce type of inherited pain. The search extended from Alabama to Europe, then to Beijing and then back to Alabama. Affected individuals within these families have a hyperactive mutant gene—a pain gene—which makes them feel intense burning pain. Their disease is called “inherited erythromelalgia” (pronounced a•rith•ro•mel•AL•ja). The pain is often described as excruciating, and people harboring the broken gene feel as if they are on fire. Figure 1.1, drawn by a person with erythromelalgia to depict her pain, tells the story better than words.
Figure 1.1 Drawing, entitled A Constant Battle, submitted to The Erythromelalgia Association for their 2012 art contest, depicting the pain of erythromelalgia. Reproduced with permission of Jennifer Beech and The Erythromelalgia Association.
To explore the physiological basis for chronic pain, and ultimately to cure it, we need to understand where it comes from. Throughout our body we have specialized pain-signaling nerve cells that innervate the body surface and organs and act as sentries. These pain-signaling cells act as a protective, early-warning system. They sense the presence of threatening stimuli—dangerous heat or cold, pinch, pinprick, pressure, or chemical irritant—and evoke protective responses like pulling a threatened limb away. In response to these stimuli, these nerve cells produce nerve impulses that carry the pain signal from our body surface and organs to the spinal cord, where the message is relayed to the brain, where pain enters consciousness and takes on its unpleasant quality. In the absence of threatening external stimuli, these pain-signaling neurons are normally quiet, and we do not have a sensation of pain. But after these cells are injured by trauma or disease, they can become hyperactive, taking on a life of their own and sending pain signals to the brain even when a threatening stimulus is not there. The result is a sensation of being burned when there is no flame or hot object touching the body, or of sticking pain when there is no pointy object injuring the body. This abnormal form of pain is called neuropathic pain; it is defined by scientists as pain due to disease or dysfunction of sensory neurons within the nervous system.
Neuropathic pain is common and can erode the quality of life in people with disorders as diverse as diabetes, traumatic nerve injury, a complication of shingles called postherpetic neuralgia, and peripheral neuropathy that arises as a complication of cancer chemotherapy. A report by the Institute of Medicine of the National Academy of Sciences (Committee on Advancing Pain Research, Care, and Education, Institute of Medicine, National Academy of Sciences 2011) estimated that approximately 100 million adults in the United States are burdened by various types of chronic pain, at an estimated annual economic cost of more than $500 billion. Chronic pain occurs, in fact, in more patients than cancer, heart disease, and diabetes combined. Amplifying the impact, chronic pain is often unresponsive or responds only partially to treatment with existing medications. Many of these medications cause side effects that can include double vision, confusion, sleepiness, loss of balance, gastrointestinal irritation, or constipation. And some of them can cause addiction. There is a pressing need for new, more effective pain medications devoid of these side effects.
The stories of five ordinary people show just how devastating neuropathic pain can be:
Now, consider a final and very different case history:
This book describes the search for a gene controlling pain. The human genome—more than 20,000 genes—contains a molecular blueprint for the body. Each of the genes contains the instructions for making a protein. And genes, in some ways, are easier to study than proteins. The chapters in this book tell the story of the hunt, within the labyrinth of genes that make up the human genome, for a gene pointing to a key protein molecule, a master switch that turns pain on or off.
No two people—except for identical twins—are exactly the same. Two patients with diabetes may both suffer from weakness and atrophy of the muscles due to injury of their nerves called peripheral neuropathy. In both, the reflexes are blunted by their nerve disease so that the neurologist’s hammer cannot trigger a response. But one of these patients is debilitated by pain that almost never abates, while the other notices numbness and mild tingling but does not seek medical attention and goes dancing on the weekend. 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. Might the difference lie in their genes?
When a gene goes awry, the protein that it produces may be changed. Some alterations in genes produce especially dramatic changes in the proteins they encode. The changes in these altered genes are commonly known as “mutations.” Mutations cause hereditary diseases, but, in addition to the negative connotation that we associate with them, mutations can act as guideposts for researchers.
So, why search the globe for families containing people who feel they are on fire? Certain patterns of disease, like its presence in multiple generations, suggest parent-to-child passage and heighten the likelihood that a mutation is at work. The history of modern medicine teaches us that rare families—families carrying uncommon mutations—can point to critically important genes and the proteins they produce, thereby identifying critically important molecular players in a disease. Some mutations, identified in families with rare inherited diseases, can teach us important lessons that are relevant to common disorders.
Families with rare inherited diseases, and the mutations that cause them, can also point us in the direction of new therapies, including new treatments for common disorders in “the rest of us.” As one example, some readers of this book may take medications called statins, which control the levels of certain lipids within our blood. The introduction of statins into medical practice has substantially reduced the incidence of heart attacks and strokes. Development of the statins had its roots in genetics. A key step was the discovery of rare families in which heart disease occurred prematurely due to a genetic disorder—inherited hypercholesterolemia—in which high levels of cholesterol plug up blood vessels. This provided a basis for the identification of mutations in specific genes, and this, in turn, pointed the way to the culprit molecules. And this permitted the development of a new class of statin drugs that targeted these culprit molecules, effectively lowering the incidence of heart disease in the broad general population.
There was still another reason for the search for families with inherited pain. The development of new medications consumes the time and energy of researchers and is expensive. And it is scientifically challenging. It can take fifteen years or more—and a lot of luck—for a new molecular entity (a potential drug) to progress from early studies at the laboratory bench to the clinical marketplace. It has been estimated that the cost of developing a new medication, from early work in the laboratory until it is introduced into the clinic, is about $1 billion. Each clinical trial can cost tens of millions of dollars. A clinical trial also requires patients as “human subjects.” In many cases this means that there is some other clinical trial that cannot be carried out, since these studies compete for human subjects as well as dollars. A clinical trial done to test drug A may mean that a trial for drug B cannot be completed. Given the investment of time and effort and this immense cost, there is not much room for false starts—which takes us back to this question: In developing a new medication, which of the myriad molecules within the body should be targeted?
Imagine what we could learn if researchers had, in hand, knowledge of a pain gene—a specific gene that could turn pain on or off. At a minimum that would teach us new lessons about how—in a fundamental way—pain arises. And, ultimately, it might facilitate the development of new treatments that would more effectively relieve pain.
This book is about the search for that gene.