Esther M. Sternberg, M.D., is Director, Integrative Neural Immune Program, National Institute of Mental Health, National Institutes of Health. She was trained in rheumatology at McGill University and practiced medicine in Montreal before returning to a research career and teaching at Washington University in St. Louis. The winner of the Public Health Service Superior Service Award and President of the International Society for Neuroimmunomodulation, Dr. Sternberg has written over one hundred scientific papers, reviews, and book chapters on the subject of brain-immune connections. She lectures nationally and internationally on emotions, health and disease.

Preface	p. xi
Emotions and Disease: Molecules and Ancient Myths	p. 1
Where Do Emotions Come From?	p. 15
The Dirty Soup Beyond Our Skin: How the Immune System Defends Against the Outside World	p. 39
Putting the Mind and Body Back Together Again	p. 55
It's a Two-Way Street: The Immune System Talks to the Brain and the Brain Talks Back	p. 79
When the Brain-Immune Communication Breaks Down	p. 93
Can Stress Make You Sick?	p. 109
Connecting to Others: Relationships and the Course of Disease	p. 133
Can Believing Make You Well?	p. 159
How the Immune System Changes Our Moods	p. 181
Prometheus Unbound: What Does the Future Hold?	p. 197
Bibliography	p. 213
Index	p. 233
Table of Contents provided by Syndetics. All Rights Reserved.

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Excerpts

The Balance Within

CHAPTER·1·

Emotions and Disease

Molecules and Ancient Myths

Nestled at the top of a brown stony hill above the modern Cretan village of Lentas, at the intermingling of cool sage mountain air and warm salt sea breezes, are the ruins of an ancient temple to Asclepius, the Greek god of healing. The temple's two remaining pillars stand like sentinels marking north and south, forming the narrow end of a once oblong colonnade, built in exact alignment with the sun's path. It is a few meters above what was once the source of a natural spring; ancient priests used these waters, and prayer, music, sleep, and dreams to cure the sick. The warm white marble columns still reflect the early morning sun against the blue Mediterranean below. On a flat terrace, just beyond the temple, a mythical animal with the head of a horse and body of a fish, patterned out of smooth, round, white and black pebbles, hides the floor of the priests' coffers of this once rich sanctuary. And the village people, who still live as one with the rhythms of the sea and sun, know, as their ancestors knew, that emotions and health are one.

As the wind and sun eroded that first ancient shrine, and dried its healing source, something also happened to the world beyond the village. Our faith in the healing power of the spirit also waned; and the god of science and medicine became a much harder, more impersonal god than the fatherly Asclepius. When did we modern scientists and physicians lose the knowledge that was so much a part ofthese ancient teachings of medicine? And why has the road back to acceptance of this wholeness taken so many centuries to travel?

The temple and the ancient town below, once a busy crossroads port called Leban, first stopping point between Egypt and Greece, flourished around 400 B.C. This was about the time that the great Greek physician Hippocrates, whose oath still underlies the principles of modern medicine, taught that health lay in a balance. And Asclepius, the Greek god of healing, with his daughters, Hygeia and Panacea, symbolized all that was essential in this balance--healthy diet, pure waters, exercise, and support of friends and family. The concept has survived to this day: "hygiene," or cleanliness, is still the first step in preventive medicine, and "panacea" still means heal-all. But essential, too, were the emotions, as well as soothing activities that calmed them--sleep, music, and prayer. So integral to the healing of the body was the mind that the god of medicine carried a staff with the symbols of both intertwined: Asclepius carried in his left hand the caduceus, a wooden staff with a serpent curled around it, an ancient symbol of body and soul, and today the universally recognized symbol of medicine.

Facing east, with your back to the pillars of the ancient temple, squinting into the already hot morning sun, you can see a tiny stone church just 100 meters away. Amidst the scrub and stones and fallen pillars, a lone gardener lovingly tends the shrine. To reach it, scramble over the loose rocky soil, down the steep terraced ridges of the temple, past where the ancient source used to run. Climb up an embankment, through lavender and prickly bramble, and you are there. It sits atop its own little hill, amidst another pile of ruins--also the remains of a place of worship, built later than the temple but before the newer church. Here the gardener pulls the weeds from between the cracks and crevices of the flat square stones paving the earth, stones that must have formed the floor of the Byzantine basilica that stood here more than 1200 years ago.

The newer church, itself nearly 100 years old, is not much larger than a small room and not much taller than a man. Bending low to enter the single doorway, you find the impact of the cool air within to be an immediate relief from the unrelenting sun that beats downupon the hillside. As your eyes acclimatize to the darkness, you realize that you are surrounded by a surprising array of brightly painted red, gold, silver, black, and brown icons--faces of the Virgin Mary and the baby Jesus. The flicker of votive candles left by the devout villagers lights the pictures, large and small. The villagers come alone to pray or throng here in large numbers whenever a priest passes through the tiny village on his rounds. Old and young alike scramble up the steep, well-worn footpath, bending almost horizontally to grasp at branches, steady their gait, and keep from sliding backward as the stony soil gives way.

But now, you are alone. The gardener has left. Only swallows remain, flitting in and out from shaded eaves under the church's red-tiled barrel roof. Peering through the narrow door toward the shining sea and village far below, you glimpse the sun, almost straight above. It must be close to noon--too hot for any mortal being.

Clambering down the hillside, past riotously bright red, pink, and fuchsia bougainvillea attached to white stucco walls, you reach the village square. The villagers are all asleep. Closer to the sea, the salty and faintly fishy smell mingles with the eucalyptus whose branches provide the first shade over the steepening lane. At the last row of houses, a flight of narrow, uneven stucco steps twist like a pile of children's blocks to the pebbly beach below. Finally, in the narrow spaces between the sharp white walls, is the sea--a blue so intense, so azure, so deep, that it seems unreal.

Here, along the cove, the fishermen live in balance with the elements. The rhythms of their lives are set by the rhythms of the day and of the seasons. They watch for signs of storm, and tide, to know when to tie their boats closer in and tighter to the shore. And they watch the changing seasons, to know when to retreat to a town high up in the mountains behind the village, when the rainy season comes. They watch the stars and know, just as their forbears knew, the names of all the constellations and of our galaxy. For here, by the shore in the dark, dark night, you can see the Milky Way as clearly as did the ancient Greeks, who named this faint spill of white that stains the night skygalaxias,fromgalactos,the milk that it resembles.

Today, the villagers have adapted, but only somewhat, to the trickling tourist trade--the few brave souls who have trekked over the daunting mountains that hem this tiny village up against the sea. Each house along the pebbled cove sports a porch with brightly colored tables and chairs, painted blue or red or green. Here villagers and tourists wile away the day sipping thick Greek coffee and lemonade made with water from what is left of the source. They nibble at Greek salads, creamed eggplant, cucumber yogurt "tzatzikis," or grapeleaf-wrapped dolmades, and watch the sea. The old men, long since unable to gain a living from their boats, sit at their favorite tables, playing backgammon, and time and again beat the younger men, stronger than they, but with yet much to learn about the game. There is a richness to the social fabric of this place: children run free, but are watched by a dozen mothers' eyes; gnarled old men and women,though walking with canes, are still able to climb the steep slopes daily to visit neighbors and to pray at the shrine above the town. What happened to our modern world, where isolation has replaced social support, where technology has broken the bond between doctor and patient in healing, where the role of emotions in health and disease has been too often cast aside?

Perhaps it was the discoveries of twentieth-century physicists--the ever-smaller particles that make up the physical universe--that turned our thinking away from emotions and toward a more quantifiable physical world. "If you can't measure it, it isn't real" became an unspoken dogma of modern science and by extension of medicine. Perhaps it was the discoveries of the sixteenth-century anatomists--the abnormalities of anatomy underlying many diseases--that made us assume that illness could spring only from concrete and visible distortions of anatomy, not ephemeral and invisible distortions of mind. "If you can't see it, it isn't real" became another tenet of modern medicine. Or was it Copernicus's revolutionary doctrine of an earth revolving around the sun, and not vice versa, that made us all discard the idea that invisible, uncontrollable fate--and by extension, invisible, uncontrollable emotions--held power over our daily lives, our health, and our deaths?

Most historians and philosophers agree that it was the teachings of the seventeenth-century French philosopher René Descartes that ushered in the thinking of the modern age and began the unraveling of the ancient link between emotions and health. In his reaction to the religious wars and the resulting turmoil that spread across Europe for most of his adult life, Descartes formulated the concepts of rationalism and the necessity of visible proof that were to become the founding principles of modern science. In that era, emotions seemed a thing of magic, fleeting and undefinable in the framework of the science of the day. In Descartes's orderly division of the world into rational and irrational--provable and unprovable--emotions and their relationship to health and disease clearly fell into the latter domain. And there they remained until scientific tools powerful enough to challenge the categorization could rescue them.

Whatever the precise combination of philosophies that contributed to this mind-set, the latter-day philosopher-scientists left alegacy so ingrained in their successors' way of doing science that many scientists don't even realize it's there, and they certainly don't recognize where it came from. There has been, for example, an assumption at all levels of science, from basic laboratory to national research funding institutions, that unless a study is focused and narrow, it is bad science. Similarly, if the work does not fit into a clearly defined and narrow discipline, it is bad science. This tide is turning now. But as recently as the 1990s, some leading scientific policy makers and academicians could still be heard to say that stress research had no place in the structure of AIDS research funding, some have even been quoted as calling it "puffery." Such resistance to new ideas has many precedents in science. James Lister and Louis Pasteur were at first excluded from academic honor societies and laughed at for their theories on sterilization, vaccination, and pasteurization. But there was yet another reason for the academic medical community's rejection of the science of the mind-body connection. Beyond its newness is its oldness. That it is embedded in the popular culture made serious scientists shy away from it for many years, for fear they would be branded fakes.

Only very recently has this mind-set begun to thaw--with considerable pressure from the popular culture. The overemphasis on a narrow focus, combined with a fascination with technology to the exclusion of the personal touch, has been a toxic mix for the practice of medicine. It has led the public to seek alternative treatments, which in the right circumstances can help, but in the wrong can harm. The plethora of therapies that have sprung up to fill the vacuum, where science and academic medicine have failed the public, have caused confusion for the consumer, who must try, without expertise, to make a judgment on the validity of each cure. But patients, the very people for whom medical research is intended, disillusioned with the narrowness of scientific thinking, have insisted on a wider view. And by their embrace of alternative practices, they are pushing science from without. At the same time, equally widespread advances in technology, enabling researchers to track the pathways of mind and immunity, are finally overcoming the resistance of the scientific community to the notion that the brain and the immune system can and do communicate. In this melee, scientists in general are finally being roused to the necessity of integrating research findings, and in medicine specifically, of doing so with the whole person in mind. But without recentadvances in the sciences of mind and body--in neuroscience and immunology, in endocrinology and psychiatry and rheumatology--it is likely that scientists and academic physicians would still be where they were a decade ago, mired in the focused, narrow thinking of seventeenth-century rationalism.

Because the assumptions of rationalism are so integral to scientific thinking, it is not surprising that it took the development of sophisticated technologies to convince scientists, through the language of science, that such mind-body connections are real. Until the last decade we simply did not have the tools capable of demonstrating the physical and molecular underpinnings of both emotions and disease. And without these, we could not begin to understand the biological basis of the healing power of the ancient Asclepions. In the absence of measurable physical evidence, the effects of such unquantifiable forces on health were dismissed as imaginary. But medical science is now at a crossroads of discoveries that finally allow us to piece together the mosaic of the biological basis and physiological effects of sleep, relaxation, and even prayer. We can finally begin to understand, and therefore believe, what the ancient priests knew intuitively about the curing effects of these activities. And by understanding these connections in modern terms, in the language of molecules and nerve pathways, electrical impulses and hormonal responses, scientists can finally accept that such effects are real.

Think for a moment of what it is like to be sick. The boundaries of your world shrink to the edge of your mattress. Light filters through half drooping eyelids, and the cool sheets rub against your hot skin. A bowl of soup sits abandoned on the nightstand. The gulf of floor between you and the bathroom door seems as daunting as a desert trek. You will yourself to get out of bed, but each muscle aches and the weakness is overwhelming. You fall back against the pillows, exhausted, and demoralized.

Illness can be teased apart into its discrete components: fever, fatigue, sleepiness, weakness, sadness, loss of interest in the environment, loss of appetite for food and sex, and an overwhelming desire to be still. Each of these feelings can be explained by the effects on the brain of various molecules released from immune cells during aninfection. But we usually describe all these components with one parsimonious phrase: "feeling sick." These two words compactly convey the notion that our awareness of being ill has a sensory component, such as pain, and an emotional component, such as feeling sad.

The notion of feelings as an integral part of illness is universal--not only across continents and peoples, but across the divide of time that separates us from our ancestors. For thousands of years, humankind has been fascinated by the apparent connection between emotions and disease. The link that connected early peoples both to their mysterious, unexplainable, often threatening outside world, and to its apparent precipitation of disease, was their emotions. Even before the Greeks were ministered to in the soothing surroundings of the Asclepion, the belief that emotions could cause disease held sway in popular culture. We encounter it as far back as the Hittite king who developed paralysis and speech loss after a frightful thunderstorm, or in the fifteenth-century belief in monster births if a pregnant woman was exposed to a fright. This belief carried through to the nineteenth century and, in transmuted form, on into the twentieth century, in grandmother's warning that if mother spilled coffee on her leg, baby would be born with a birthmark on the thigh. Although such magical thinking, rooted as it often was in the academic teachings of an earlier time, never disappeared from the popular culture, the professionals who dealt with illness tried to explain that emotion-disease connection using their best available tools. As technological advances made new investigative methods available, different aspects of this relationship were explained in one fashion or another. Some explanations turned out to be dead ends and eventually fell by the wayside, to be taken up again in the realm of popular culture--something grandmother told you that you didn't want to admit you believed. But other explanations held up to the scrutiny of scientific proof and were removed from the realm of the magical, to be ensconced in the doctrines of medicine.

The central principle of medical teaching that for a thousand years linked emotions and disease was the balance of the four humors: blood, yellow bile, black bile, and phlegm. These visible secretions were physicians' only window into the workings of the body. Imbalances in them were equated not only with disease but also with emotions. Vestiges of the concepts are buried in the words we still use to describe emotional types: sanguine, melancholy, phlegmatic, choleric.Sanguine,from the Latinsanguineusfor "blood," describes an optimistic,confident person. In the 1495Manual of Medicineby Johannes de Ketham, a sanguine person was described as fat and merry and liking Bacchus and Venus, the gods of wine and love. Not a surprising description perhaps, since these conditions--drink and love--are often associated with a rosy or blushing countenance, which is indeed caused by blood rushing to the cheeks. The opposite type in de Ketham's text, the melancholic, is a combination ofmelan,Latin for "black," andcholer,or bitter bile. A melancholic person is gloomy and bitter. But pure bile, or choler, makes one impetuous and irascible. Today, the French word forangeriscolere,and the root of the word shows up also in a "colicky" baby--one who is irritable. Phlegm, on the other hand, makes one fat and languid, slow-moving. Todayphlegmatichas come to mean stolidly calm, unexcitable, and unemotional.

Coursing through each of these words and their modern derivatives is a simple assumption that tells us a lot about the differencesacross time in the people who chose them to denote phenomena they observed. In medieval times, the humors conveyed the idea of visible, physical bodily secretions, inextricably linked to emotional responses. But over the centuries, the physical notions fell away and only the emotional elements of the words remained.

Among the forces that led to this excision of the physical from the emotional in our words and in our scientific thought were new principles of medicine. These principles grew out of the discoveries of the sixteenth-century anatomists who had begun to dissect the human body. Thus the prevailing doctrine of the balance of the four humors began to give way to the hard, visible proof of anatomy. Dissection showed that there were normal anatomical forms and connections of organs within the human body. In disease, these forms were distorted, often riddled with holes, filled with pus or blood. Disease was then defined in terms of abnormalities of anatomy. But there were many diseases in which anatomical dissection did not reveal an abnormality. These were usually diseases of emotions and the mind. In the anatomists' terms, how could these illnesses be real?

By the end of the nineteenth century, the anatomists' notion that all disease had a physical basis, so heretical in the fifteenth century, had become so much a part of the dogma of medicine that now the heretics were those who insisted that even diseases of the emotions, with no discernible anatomical basis, should be taken seriously. A struggle arose, which continues to the present day, between the physicians of the mind and those of the body--as if mind were somehow not part of body. Those concerned with the study of the mind, disillusioned with the power of anatomy to explain all illness, came up with an alternative term for diseases that could not be explained by abnormal anatomy: the "functional neuroses"--"functional" because no structural change could be found in the brain, yet no less apparent, no more difficult to diagnose than "real" disease. This discipline was rooted in the psychoanalytic theories of doctors like Sigmund Freud, himself a neuroanatomist frustrated by the inability to identify an anatomical cause for illnesses like hysteria. Freud developed his theories of psychoanalysis, based on the available knowledge of the day, to fill the void and to try to explain, in his words, "the puzzling leap from the mental to the physical." So the rift widened between those who studied the mind and those who chosethe easier, more concrete task of studying what could be seen: physical illnesses of the body.

In the late nineteenth and early twentieth centuries a new discipline arose in an effort to explain illnesses with no visible cause: psychosomatic medicine. Although now the term "psychosomatic" carries with it close to a century's worth of baggage--associations suggesting hypochondriasis and diseases that do not really exist--the term was originally meant to encompass diseases of the body (soma) caused by the spirit, or soul (psyche).Psychosomatic medicine was eventually applied in attempts to explain many physical ills in terms of the underlying psychological disturbance. The doctors who developed this school of thought, Helen Flanders Dunbar and Franz Alexander, claimed a psychological source for illnesses such as asthma, arthritis, heart disease, and gastric ulcers. But because they lacked the tools to prove such a connection, their theories fell into disrepute with the academy, which had moved on to demand stringent proof that such connections existed at a molecular and physiological level.

The teachings of psychosomatic medicine filtered into the popular culture, however, and stayed there. They joined existing beliefs about mental influences on the body and echoed back repeatedly in countless magazine articles and self-help books, even in popular song. In "Adelaide's Lament" fromGuys and Dolls,the thickly accented Adelaide sings ruefully,

In other words, just from waiting around for that plain little band of gold, A person Can develop a cold. You can spray her wherever you figure the streptococci lurk, You can give her a shot for whatever she's got but it just won't work. If she's tired of getting the fisheye from the hotel clerk, A person can develop a cold.

In modern medicine we have no difficulty in distinguishing between physical organs and the complex functions they perform, except when it comes to emotions and thought--the functions of the brain. These functions are so complex, so hard to grasp in physical terms, and until recently so hard to relate to the underlying nervoussystem structures, that the functional illnesses of emotions--the extremes of feelings that most of us have experienced in some measure at some time in our lives--could too easily be dismissed by those whose framework of proof was rigidly tangible.

What was missing at the end of the nineteenth century to explain the connection between emotions and disease was a knowledge of how these complex phenomena occurred at a level beyond what could be seen with the naked eye. It required discoveries of mechanisms that we cannot see, not with our eyes, nor even with the microscopes that did reveal to the scientists of that era the histological basis of disease. Seeing through a nineteenth-century microscope those nerve cell connections and immune cell infiltrations, or even seeing with a more powerful twentieth-century microscope the tiniest organelles within these cells, still didn't explain how these organs and cells could produce emotions nor how disturbances in them could cause disease.

It took very different kinds of technology--chemistry, biochemistry, cellular and molecular biology--to help us see the ways in which the nervous and immune systems work and communicate. We can now see that those cells--which to early microscopers appeared as immobile ghosts, fixed in their tissue firmaments--actually crawl about, meet, fuse, divide, and grow. Beneath our skins is a constantly changing world where our body's cells fashion and refashion our solid-seeming tissues. The mortar that they use to accomplish this is made of chemicals--amino acids, linked together in long chains to form proteins, which in turn form scaffoldings outside and inside the cells. These proteins are made in factories within the cell, factories we can now see with powerful electron microscopes, factories that appear like shelves and budding sacs. But even these solid-seeming structures are made of thousands of proteins and other molecules, linked together in perfectly fitting mosaics. And the directors that program all this activity are the genes within the cell's inner core. So now, too, we can actually see the DNA that makes up these genes, we can see its shape and where the molecules that control its function sit within its coils. With this knowledge, we can finally see how tightly the nervous and immune systems are linked through many interwoven strands of nerve pathways and communicating molecules. And once we understand that, it is not so difficult to imagine that forces that might perturb one system would have powerful effects on the functioning of the other.

We have the tools, then, to see beyond the limits of the microscopic images of the histologists of the nineteenth century, deep within the cell, to the very genes that make it function. At the same time we can move beyond the limits of the outlines of anatomy to see, with computer imaging techniques, the living human brain at work. By combining these tools we can understand how the brain receives signals from the outside environment and how these signals are processed into perceptions as well as emotional, physiological, and hormonal responses. And with advances in cellular and molecular biology, we can piece together how such nervous system and hormonal changes can affect our susceptibility to disease. By parsing these chemical intermediaries, we can begin to understand the biological underpinnings of how emotions affect diseases: viral or bacterial infectious diseases, such as AIDS and tuberculosis; inflammatory diseases, such as rheumatoid arthritis and lupus; and illnesses in which extreme fatigue goes along with aching muscles and joints, such as fibromyalgia and chronic fatigue syndrome.

Through this very research, scientists are finding that the same parts of the brain that control the stress response, for example, play an important role in susceptibility and resistance to inflammatory diseases such as arthritis. And since it is these parts of the brain that also play a role in depression, we can begin to understand why it is that many patients with inflammatory diseases may also experience depression at different times in their lives. Thus, the psychosomatic notion that inflammatory and allergic diseases originate in a disordered upbringing and repressed emotions can now be reexamined in more precise physiological terms. Rather than seeing the psyche as the source of such illnesses, we are discovering that while feelings don't directly cause or cure disease, the biological mechanisms underlying them may cause or contribute to disease. Thus, many of the nerve pathways and molecules underlying both psychological responses and inflammatory disease are the same, making predisposition to one set of illnesses likely to go along with predisposition to the other. The questions need to be rephrased, therefore, to ask which of the many components that work together to create emotions also affect that other constellation of biological events, immune responses, which come together to fight or to cause disease. Rather than asking if depressing thoughts can cause an illness of the body, we need to ask what the molecules and nerve pathways are that cause depressingthoughts. And then we need to ask whether these affect the cells and molecules that cause disease. In order to find the answers to these questions, we must know something about the brain's nerve pathways that underlie emotional responses and also about the body's normal immune responses to chemical or physical threats.

Since new research is showing that inflammation is an important part of diseases previously thought not to have an inflammatory basis--for example, Alzheimer's disease and heart disease--understanding the brain pathways that predispose either to susceptibility or resistance to inflammation will open up new ways to successfully treat an even wider range of illnesses than previously imagined. We are even beginning to sort out how emotional memories reach the parts of the brain that control the hormonal stress response, and how such emotions can ultimately affect the workings of the immune system and thus affect illnesses as disparate as arthritis and cancer. We are also beginning to piece together how signals from the immune system can affect the brain and the emotional and physical responses it controls: the molecular basis of feeling sick. In all this, the boundaries between mind and body are beginning to blur, even for the academics who had for so long worked to keep those boundaries sharp. These questions can now be answered at a level of detail that will offer new treatments for disease and new ways of interacting with the stresses in our environment that we cannot control.