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Chapter 1
THE RECEPTOR REVOLUTION: AN INTRODUCTORY LECTURE
Scientists, by nature, are not creatures who commonly seek out or enjoy the public spotlight. Our training predisposes us to avoid any kind of overt behavior that might encourage two-way communication with the masses. Instead, we are content to pursue our truth in windowless laboratories, accountable only to members of our highly exclusive club. And although presenting papers at professional meetings is encouraged, in fact required, it's rare to find one of us holding sway to standing-room-only crowds, laughing, telling jokes, and giving away trade secrets.
Even though I am a long-standing club member and bona fide insider myself, I cannot say that it has been my trademark to follow the rules. Acting as if programmed by some errant gene, I do what most scientists abhor: I seek to inform, to educate, and inspire all manner of people, from lay to professional. I try to make available and interpret the latest and most up-to-date knowledge that I and my fellow scientists are discovering, information that is practical, that can change people's lives. In the process, I virtually cross over into another dimension, where the leading edge of biomolecular medicine becomes accessible to anyone who wants to hear about it.
This mission places me in the public spotlight quite often. A dozen times a year, I am invited to address groups at various institutions, and so, when not engaged in my work at Georgetown University School of Medicine, where I am a research professor in the Department of Biophysics and Physiology, I go shuttling from coast to coast, sometimes even crossing the great blue waters. It was never my plan to become a scientific performer, to act as a mouthpiece for educating the public as well as practitioners in the alternative health movement, so wed was I for most of my career to the mainstream world of the lab and my research. But it's been a natural evolution, and I am now at home in my new role. The result of translating my scientific ideas into the vernacular seems to have been that my life in science and my personal life have transformed each other, so that I have become expanded and enriched in myriad unexpected ways by the discoveries I've made, the science I've done, and the meaning I continue to uncover.
Writing this book was an attempt to put down on paper, in a much more detailed and usable form, the material I've been presenting in lectures. My goal in writing, as in speaking, was twofold: to explain the science underlying the new bodymind medicine, and to give enough practical information about the implications of that science, and about the therapies and practitioners embodying it, to enable my readers to make the best possible choices about their personal health and well-being. Perhaps my journey, intellectual as well as spiritual, can help other people on their paths. And now -- on with the "lecture"!
ARRIVAL
Whenever possible I try to arrive at the lecture hall early, before the members of the audience take their seats. I get a thrill out of sitting in the empty room, when all is quiet and there exists a state of pure potentiality in which anything can happen. The sound of the doors swinging open, the muffled voices of the crowd as they file slowly into the room, the clinking of water glasses and screeching of chairs -- all of this creates a delightful cacophony, music to my ears, the overture for what is to come.
I watch the people as they move toward their seats, finding their places, chatting with a neighbor, and getting comfortable, preparing themselves to be informed, hopefully entertained, unaware that my goal is to do more: to reveal, to inspire, to uplift, perhaps even to change lives.
"Who's this Candace Pert?" I may ask, retaining my anonymity as I playfully engage the person now seated next to me. "Is she supposed to be any good?" The response is sometimes informative and always amusing, allowing me a brief entry into the thoughts and expectations of those I am about to address, I nod knowingly in response and pretend to arrange myself more comfortably, more attentively.
I often find myself addressing very mixed audiences. Depending on the nature of my host's organization, the crowd is either weighted toward mainstream professionals -- doctors, nurses, and scientific researchers -- or toward alternative practitioners -- chiropractors, energy healers, massage therapists, and other curious participants -- but frequently includes members from both camps in a blend that can best be described as the Establishment meets the New Paradigm. This sort of composition is very different from the more homogeneous audiences present at the hundreds of talks I've given over the past twenty-four years to my fellow scientists, colleagues, and peers. For them, I deliver my more technical remarks in the language of the club, not needing to translate the code we all understand. I still address such groups, making the yearly round of scientific meetings, but now I also venture into a foreign land, where few of my fellow scientists dare -- or wish -- to go.
Breathing deeply for a moment or two, I relax into my seat and close my eyes. My mind clears as I offer a brief prayer to enter a more receptive state. Calling on an intuitive sense of my audience's expectations and mood, I can feel the wall coming down, the imaginary wall that separates us, scientist from lay person; the expert, the authority, from those who do not know -- a wall I personally stopped believing in some time ago.
THE AUDIENCE
As the room fills, I can feel the excitement building. When I open my eyes and glance around at one of these mixed crowds, I notice first that, in marked contrast to the more scientific gatherings, there are usually large numbers of women present. It still surprises me to see so many of them, dressed beautifully in their flowing California-style robes of many colors. I am always stunned by the many shades of purple in their dress, more shades than I ever knew existed! Then, looking beyond the surface, I try to assess the various components of my audience and what might have motivated them to come today.
My attention goes first to the doctors and other medical professionals, whose contingent is almost always dominated by males. The men sit erect in their well-tailored dark suits and crisp white shirts, while nearby their female counterparts look officiously around, checking the room for the faces of their colleagues.
Scattered more sparsely throughout the room are the neophytes, earnest young men and women with packs on their backs and dreams in their eyes. Their posture is perky and eager, revealing their sincerity and also their uncertainty about what they want or where they are going.
As the room settles and voices are hushed to a low din, I wonder: What do all these people expect me to tell them? What do they want to know, what are they hoping for?
Some are here because they saw me on Bill Moyers's PBS special Healing and the Mind, a program that also included segments with Dean Ornish, Jon Kabat-Zinn, Naomi Remen, and a number of the other doctors, scientists, and therapists who are trying to make the same mind-body connections that have become my life's work. Being interviewed by such a well-informed, receptive journalist made it possible for me to speak of the molecules of mind and emotion with a passion and humor not ordinarily associated with medical research scientists. I tried to make it easy for a television audience to understand the exciting world of biomedicine, molecular theory, and psychoneuroimmunology, revealing information usually shrouded by an impenetrable language, letting them know that they have a stake in understanding this body of knowledge, because it could give them the power to make a difference in the state of their own health.
The physicians, nurses, health care professionals -- what brings them out? Have they touched on some new situation that their current knowledge cannot explain? Many of them know me as a former chief of brain biochemistry who toiled at the National Institutes of Health for thirteen years, demonstrating and mapping biochemicals I later came to call the physiological correlates of emotion. Some may know that I left the National Institutes of Health when I developed a powerful new drug for the treatment of AIDS and couldn't get the government interested. All of them seem to be aware that science marches on, and that much of what they were taught in medical school twenty years ago, even ten years ago, is no longer current, even applicable. They know that my work is in a breaking field -- no less a chronicler of contemporary culture than Tom Wolfe himself has pronounced neuroscience the "hottest field in the academic world" in a recent issue of Forbes -- and that it's just now finding its way into medical schools around the world.
Then there are the many massage therapists, acupuncturists, chiropractors -- the so-called alternative medicine practitioners who offer their patients approaches that are not part of the mainstream. I'm aware that these people have been marginalized for years, rarely taken seriously by the powers that be -- the medical schools, insurance companies, the American Medical Association, the Food and Drug Administration -- although it is well documented that the public spends billions yearly on their services. Later, in the Q&A sessions that follow the talks, they tell me they believe I have done the research that will lead to the validation of their theories, their beliefs. They have read about my theory of emotions, about how I have postulated a biochemical link between the mind and body, a new concept of the human organism as a communication network that redefines health and disease, empowering individuals with new responsibility, more control in their lives.
The philosophers, the seekers, they're here too. Some are very silent -- listeners, not talkers -- these pale, earnest young men and women who tell me after the lecture that they've been traveling in India or living in Asia. They see my work as proof of what their gurus and masters have long been saying, and they want more answers, perhaps about the meaning of it all. Maybe they've heard me quoted as the scientist who said "God is a neuropeptide." They know I'm not afraid to use what most scientists consider a four-letter word -- soul -- in my talks, and they want me to address their spiritual questions today.
Many come simply because they are curious. Perhaps they've heard of my reputation as a young graduate student who laid the foundation for the discovery of endorphins, the body's own pain suppressors and ecstasy inducers. Or they may know me as the young woman who was passed over for a prestigious pre-Nobel Prize and dared to challenge her mentor for the recognition she felt she deserved. They may recall how the resulting front-page controversy exposed a system that was sexist and unjust at its core, and caused a shake-up that embarrassed a medical dynasty.
Others are here because they need to have hope. The sick, the wheelchair-bound, I see them positioned on the aisles, near the doors. They know I've been on the cutting edge with my research, crossing disciplines and researching for breakthroughs in cancer, AIDS, mental illness. I always feel a little nervous when I see them sitting in my audience. Are they expecting me to deliver their miracle cure like a preacher at a revival meeting? Hope is a dirty, rarely uttered word in the circles I frequent, and it still tugs uncomfortably at my self-image as a scientist. To think I'm being viewed as a healer -- God forbid, a faith healer! Yet I can't ignore the expressions of desperation and suffering that I see on their faces. Information. Yes, at least I can give them that, something they can use in seeking alternatives, these people for whom mainstream medicine offers no further answers, no treatment, no hope.
Regardless of their profession, orientation, or expectations emotional or intellectual, I've come to believe that most of the lay people who find their way to my lectures are hoping to hear science demystified, de-jargonized, described in terms they can understand. They want to be more in control of their own health and to learn more about what is going on in their own bodies, and they have been deeply disappointed, disillusioned by the failure of science to deliver on its promises to provide cures for the major diseases. Now they want to take back some power into their own hands, and they need to know about what the latest scientific discoveries mean for obtaining optimal health.
Perhaps you, my reader, see yourself in one or more of the groups described above. If so, I hope for your sake, as I always hope for the members of my audiences, that some part of the information presented in this book will make a difference in your life.
TAKING THE STAGE
A sudden hush descends on the room, catching me off guard, and my head turns as I glimpse a figure walking slowly across the stage toward the spotlit podium. What follows is generally a lavish detailing of my list of accomplishments. I feel genuinely moved by the appreciation expressed by my host or hostess, but always a bit embarrassed and undeserving of such flattering words.
Over the years, I've learned to keep my ego reigned in by saying a quiet blessing during these introductory remarks. I ask that I not be cowed by my mission, nor swept up in it. I remind myself that, in spite of the spotlight I am about to step into, first and always I am a scientist, a seeker of the truth -- not a rock star! I silently vow that I won't let any of this go to my head -- although that could easily happen, and did happen occasionally at one time.
At last I hear my name and rise from my chair to begin the long walk onto the stage. I remember to breathe deeply as I pass the front row and feel all eyes in the room turn to focus on me. A few whispered words reach my ears as I move along: "There she is! Is that her? She doesn't look like a scientist!"
What did they expect? I wonder with an inward chuckle. I am still a woman, a wife, and a mother. Don't I fit their pictures of the scientist? Of course, they have their own ideas, and many of them fit the standard cliche of the conservatively dressed, intense-looking, usually male scientist. Not too long ago, I wore those serious little boxy suits, the dress-for-success uniform, conforming to the more buttoned-down image people expect. But now, my own transformation is boldly reflected in the way I present myself, an image that better matches my message these days. In keeping with the evolution of my scientific ideas, my dress has evolved so that I now look more like the ladies in the flowing robes, my clothes looser and more colorful, more comfortable, even more purple! These days I dare to be more outrageous, although those who know me insist that outrageousness has always been the hallmark of my personality, however submerged I've tried to keep it at times to survive.
Taking my place at the podium, I wait while the technicians fumble with my mike and make last-minute adjustments to the projection screen at my side. As I look out on the sea of upturned faces, I am struck by how perfectly still people sit. I know they won't move until I crack a joke, giving them permission to enjoy themselves and explode in laughter, animating the room and filling it with energy.
My audience is ready and so am I -- hundreds, sometimes thousands of people are seated before me waiting for my words. I take one last minute to focus inwardly on my mission: to tell the truth about the facts that were discovered by my colleagues and myself. First and foremost, I am a truth-seeker. My intention is to provide an understanding of the metaphors that express a new paradigm, metaphors that capture how inextricably united the body and the mind really are, and the role the emotions play in health and disease.
The house lights dim as I clear my throat and my first slide comes up on the screen.
SETTING THE TONE
There is something incredibly intoxicating about standing in front of a huge room full of people who are all laughing uproariously. I have become quite addicted to this experience, ever since 1977 when I gave a lecture to the National Endocrine Society and accidentally brought down the house with a joke that was intended to cover a mistake I'd made. Now I don't waste any time. I start right off with a cartoon that never fails to elicit hearty, if sometimes nervous, laughter.
My first slide looks like this: [John King, 1948-1997. See -- it wasn't psychosomatic]
I use this joke to make the point that as a culture we are all in denial about the importance of psychosomatic causes of illness. Break the word psychosomatic down into its parts, and it becomes psyche, meaning mind or soul, and soma, meaning body. Though the fact that they are fused into one word suggests some kind of connection between the two, that connection is anathema in much of our culture. For many of us, and certainly for most of the medical establishment, bringing the mind too close to the body threatens the legitimacy of any particular illness, suggesting it may be imaginary, unreal, unscientific.
If psychological contributions to physical health and disease are viewed with suspicion, the suggestion that the soul -- the literal translation of psyche -- might matter is considered downright absurd. For now we are getting into the mystical realm, where scientists have been officially forbidden to tread ever since the seventeenth century. It was then that Rene Descartes, the philosopher and founding father of modern medicine, was forced to make a turf deal with the Pope in order to get the human bodies he needed for dissection. Descartes agreed he wouldn't have anything to do with the soul, the mind, or the emotions -- those aspects of human experience under the virtually exclusive jurisdiction of the church at the time -- if he could claim the physical realm as his own. Alas, this bargain set the tone and direction for Western science over the next two centuries, dividing human experience into two distinct and separate spheres that could never overlap, creating the unbalanced situation that is mainstream science as we know it today.
But much of that is now changing. A growing number of scientists recognize that we are in the midst of a scientific revolution, a major paradigm shift with tremendous implications for how we deal with health and disease. The Cartesian era, as Western philosophical thought since Descartes has been known, has been dominated by reductionist methodology, which attempts to understand life by examining the tiniest pieces of it, and then extrapolating from those pieces to overarching surmises about the whole. Reductionist Cartesian thought is now in the process of adding something very new and exciting -- and holistic.
As I've watched as well as participated in this process, I've come to believe that virtually all illness, if not psychosomatic in foundation, has a definite psychosomatic component. Recent technological innovations have allowed us to examine the molecular basis of the emotions, and to begin to understand how the molecules of our emotions share intimate connections with, and are indeed inseparable from, our physiology. It is the emotions, I have come to see, that link mind and body. This more holistic approach complements the reductionist view, expanding it rather than replacing it, and offers a new way to think about health and disease -- not just for us scientists, but for the lay person also.
In my talks, I show how the molecules of emotion run every system in our body, and how this communication system is in effect a demonstration of the bodymind's intelligence, an intelligence wise enough to seek wellness, and one that can potentially keep us healthy and disease-free without the modern high-tech medical intervention we now rely on. In this book I've tried to give pointers about how to tap into that intelligence, and, in the Appendix, I've provided a listing of organizations that practice various aspects of bodymind medicine, so that those of you who are interested can get some guidance on getting the most out of that intelligence, allowing it to do its job without interference. The Appendix also contains some basic tips for healthful living, distilled from my own experience.
Shift happens! The Ptolemaic earth at the center of the universe can give way to the Copernican sun-centered theory -- but not without considerable resistance. Witness Galileo, who was brought before the Inquisition for his role in promulgating that theory over a century after it was first proposed! Or ask Jesse Roth, who in the 1980s found insulin not just in the brain but in tiny one-celled animals outside the human body. This gave the reigning medical paradigm a good shake, because everyone "knew" that you needed a pancreas to make insulin! In spite of his eminence as clinical director for the National Institutes of Health, Dr. Roth couldn't get his papers published in a single reputable scientific journal for quite a while. The reviewers sent them back with comments such as: "This is preposterous, you must not be washing your test tubes well enough." Jesse retaliated by using new test tubes and repeating his results often enough so that other researchers, intrigued by his findings, began doing similar experiments and reporting similar results.
Jesse's story illustrates one of the paradoxes of scientific progress: Truly original, boundary-breaking ideas are rarely welcomed at first, no matter who proposes them. Protecting the prevailing paradigm, science moves slowly, because it doesn't want to make mistakes. Consequently, genuinely new and important ideas are often subjected to nitpickingly intense scrutiny, if not outright rejection and revulsion, and getting them published becomes a Sisyphean labor. But if the ideas are correct, eventually they will prevail. It may take, as in the case of the new discipline of psychoneuroimmunology, a good decade, or it may take much longer. But, eventually, the new view becomes the status quo, and ideas that were rejected as madness will appear in the popular press, often touted by the very critics who did so much to impede their acceptance. Which is what is happening today as a new paradigm comes into being.
And not a moment too soon as far as the holistic/alternative health crowd is concerned. They've been disgusted with the reigning medical model for years and have, in fact, been working actively to overturn it. It's largely through their efforts that such formerly dismissed techniques as acupuncture and hypnosis have gained the credibility they now have. But even when I talk with the average health-conscious consumer, people who have no ideological animus one way or the other, I'm always astonished at how deep their anger at our present health system is. It's obvious the public is catching on to the fact that they're the ones paying monstrous health care bills for often worthless procedures to remedy conditions that could have been prevented in the first place.
In order to grasp the enormity of this revolution, you have to first understand some of the fundamentals of biomolecular medicine, which is what I like to explain at the beginning of my talks. How many of us can close our eyes and picture or define a receptor, or a protein, or a peptide? These are the basic components that make up our bodies and minds, yet to the average person, they are as exotic and remote from everyday experience as the Abominable Snowman. If we're to understand what role our emotions may play in our health, then understanding the molecular-cellular domain is a crucial first step. I also like to provide some historical context to help people understand the impact of the recent discoveries. It's a version of one of those lectures I'm putting on the page here to provide a broad overview of my work, the basic science that makes it all decipherable, and fun.
But I also have a story to tell, one that is more personal than scientific, even though parts of it do make their way into some of my more informal public lectures. The narrative of how I was transformed by the science I did, and how the science I did was inspired and influenced by my growth as a human being, especially by my experience as a woman, is as informative, I believe, as the facts of my scientific adventures, and equally as important. For this reason, I have included my personal narrative in this book, sandwiched in between sections of my lecture, where I hope it provides a perspective that enlightens as it reveals the human story behind the molecules of emotion. As befitting my own evolution, the personal and the scientific do eventually intertwine as my story progresses, underscoring the fact that science is a very human pursuit and cannot be truly appreciated if it appears as a cold and emotionless abstraction. Emotions affect how we do science as well as how we stay healthy or become ill.
THE BASICS
And now on with the science!
The first component of the molecules of emotion is a molecule found on the surface of cells in body and brain called the opiate receptor. It was my discovery of the opiate receptor that launched my career as a bench scientist in the early 1970s, when I found a way to measure it and thereby prove its existence.
Measurement! It is the very foundation of the modern scientific method, the means by which the material world is admitted into existence. Unless we can measure something, science won't concede it exists, which is why science refuses to deal with such "nonthings" as the emotions, the mind, the soul, or the spirit.
But what is this former nonthing known as a receptor? At the time I was getting started, a receptor was mostly an idea, a hypothetical site believed to be located somewhere in the cells of all living things. The scientists who most needed to believe in it were the pharmacologists (those who study and invent drugs) because it was the only way they knew to explain the action of drugs in the organism. Dating back to the early twentieth century, pharmacologists believed that for drugs to act in the body they must first attach themselves to something in it. The term receptor was used to refer to this hypothetical body component, which allowed the drug to attach itself and thereby in some mysterious way to initiate a cascade of physiological changes. "No drug acts unless it is fixed," said Paul Ehrlich, the first modern pharmacologist, summarizing what he believed to be true, even though he had no real evidence. (Only he said it in Latin to emphasize the profundity of the concept.)
Now we know that that component, the receptor, is a single molecule, perhaps the most elegant, rare, and complicated kind of molecule there is. A molecule is the tiniest possible piece of a substance that can still be identified as that substance. Each and every molecule of any given substance is composed of the smallest units of matter -- atoms such as carbon and hydrogen and nitrogen -- which are bonded together in a configuration specific to that substance, which can be expressed as a chemical formula, or, more informatively, drawn as a diagram.
Invisible forces attract one molecule to another, so that the molecules cohere into an identifiable substance. These invisible forces of attraction can be overcome if enough energy is applied to the substance. For example, heat energy will melt ice crystals, turning them into water, which will then vaporize into steam as its molecules move so fast, with so much energy, that they break loose of each other and fly apart. But the chemical formula remains the same for each state -- in this case H2O, two hydrogen atoms bonded to one oxygen atom -- whether that state is an icy solid, a watery liquid, or a colorless vapor.
In contrast to the small, rigid water molecule, which weighs only 18 units in molecular weight, the larger receptor molecule weighs upwards of 50,000 units. Unlike the frozen water molecules that melt or turn into a gas when energy is applied, the more flexible receptor molecules respond to energy and chemical cues by vibrating. They wiggle, shimmy, and even hum as they bend and change from one shape to another, often moving back and forth between two or three favored shapes, or conformations. In the organism they are always found attached to a cell, floating on the cell surface's oily outer boundary, or membrane. Think of them as lily pads floating on the surface of a pond, and, like lilies, receptors have roots enmeshed in the fluid membrane snaking back and forth across it several times and reaching deep into the interior of the cell.
The receptors are molecules, as I have said, and are made up of proteins, tiny amino acids strung together in crumpled chains, looking something like beaded necklaces that have folded in on themselves. If you were to assign a different color to each of the receptors that scientists have identified, the average cell surface would appear as a multicolored mosaic of at least seventy different hues -- 50,000 of one type of receptor, 10,000 of another, 1,00,000 of a third, and so forth. A typical neuron (nerve cell) may have millions of receptors on its surface. Molecular biologists can isolate these receptors, determine their molecular weight, and eventually crack their chemical structure, which means identifying the exact sequence of amino acids that makes up the receptor molecule. Using the biomolecular techniques available today, scientists are able to isolate and sequence scores of new receptors, meaning that their complete chemical structure can now be diagrammed.
Basically, receptors function as sensing molecules -- scanners. Just as our eyes, ears, nose, tongue, fingers, and skin act as sense organs, so, too, do the receptors, only on a cellular level. They hover in the membranes of your cells, dancing and vibrating, waiting to pick up messages carried by other vibrating little creatures, also made out of amino acids, which come cruising along -- diffusing is the technical word -- through the fluids surrounding each cell. We like to describe these receptors as "keyholes," although that is not an altogether precise term for something that is constantly moving, dancing in a rhythmic, vibratory way.
All receptors are proteins, as I have said. And they cluster in the cellular membrane waiting for the right chemical keys to swim up to them through the extracellular fluid and to mount them by fitting into their keyholes -- a process known as binding.
Binding. It's sex on a molecular level!
And what is this chemical key that docks onto the receptor and causes it to dance and sway? The responsible element is called a ligand. This is the chemical key that binds to the receptor, entering it like a key in a keyhole, creating a disturbance to tickle the molecule into rearranging itself, changing its shape until -- click! -- information enters the cell.
THE TIES THAT BIND
If receptors are the first components of the molecules of emotion, then ligands are the second. The word ligand comes from the Latin ligare, "that which binds," sharing its origin with the word religion.
Ligand is the term used for any natural or manmade substance that binds selectively to its own specific receptor on the surface of a cell. The ligand bumps onto the receptor and slips off, bumps back on, slips back off again. The ligand bumping on is what we call the binding, and in the process, the ligand transfers a message via its molecular properties to the receptor.
Though a key fitting into a lock is the standard image, a more dynamic description of this process might be two voices -- ligand and receptor -- striking the same note and producing a vibration that rings a doorbell to open the doorway to the cell. What happens next is quite amazing. The receptor, having received a message, transmits it from the surface of the cell deep into the cell's interior, where the message can change the state of the cell dramatically. A chain reaction of biochemical events is initiated as tiny machines roar into action and, directed by the message of the ligand, begin any number of activities -- manufacturing new proteins, making decisions about cell division, opening or closing ion channels, adding or subtracting energetic chemical groups like the phosphates -- to name just a few. In short, the life of the cell, what it is up to at any moment, is determined by which receptors are on its surface, and whether those receptors are occupied by ligands or not. On a more global scale, these minute physiological phenomena at the cellular level can translate to large changes in behavior, physical activity, even mood.
And how is all this activity organized, considering it is going on in all parts of the body and brain simultaneously? As the ligands drift by in the stream of fluid surrounding every cell, only those ligands that have molecules in exactly the right shape can bind to a particular kind of receptor. The process of binding is very selective, very specific! In fact, we can say that binding occurs as a result of receptor specificity, meaning the receptor ignores all but the particular ligand that's made to fit it. The opiate receptor, for instance, can "receive" only those ligands that are members of the opiate group, like endorphins, morphine, or heroin. The Valium receptor can attach only to Valium and Valium-like peptides. It is this specificity of the receptors that allows for a complex system of organization and insures that everything gets to where it's supposed to be going.
Ligands are generally much smaller molecules than the receptors they bind to, and they are divided into three chemical types. The first type of ligand comprises the classical neurotransmitters, which are small molecules with such unwieldy names as acetylcholine, norepinephrine, dopamine, histamine, glycine, GABA, and serotonin. These are the smallest, simplest of molecules, generally made in the brain to carry information across the gap, or synapse, between one neuron and the next. Many start out as simple amino acids, the building blocks of protein, and then get a few atoms added here and there. A few neurotransmitters are unmodified amino acids.
A second category of ligands is made up of steroids, which include the sex hormones testosterone, progesterone, and estrogen. All steroids start out as cholesterol, which gets transformed by a series of biochemical steps into a specific kind of hormone. For example, enzymes in the gonads -- the testes for males, the ovaries for females -- change the cholesterol into the sex hormones, while other enzymes convert cholesterol into other kinds of steroid hormones, such as cortisol, which are secreted by the outer layer of the adrenal glands under stress.
I've saved the best for last! My favorite category of ligands by far, and the largest, constituting perhaps 95 percent of them all, are the peptides. As we shall see, these chemicals play a wide role in regulating practically all life processes, and are indeed the other half of the equation of what I call the molecules of emotion. Like receptors, peptides are made up of strings of amino acids, but I'm going to save the details about peptides until a later point in my lecture. Meanwhile, one way to keep all this in your mind is to visualize the following: If the cell is the engine that drives all life, then the receptors are the buttons on the control panel of that engine, and a specific peptide (or other kind of ligand) is the finger that pushes that button and gets things started.
THE CHEMICAL BRAIN
At this point, I'd like to move away from the purely molecular level, and, with our new knowledge of the receptor and its ligands, focus for a moment on how scientists now view the brain, and how that view differs from our earlier, more limited understanding.
For decades, most people thought of the brain and its extension the central nervous system primarily as an electrical communication system. It was common knowledge that the neurons, or nerve cells, which consist of a cell body with a tail-like axon and treelike dendrites, form something resembling a telephone system with trillions of miles of intricately crisscrossing wiring.
The dominance of this image in the public mind was due to the fact that we scientists had tools that allowed us to see and study the electrical brain. Only recently did we develop tools that allowed us to observe what we may now call the chemical brain.
But, yet-to-be-named neuroscience was so focused, for so long, on the concept of the nervous system as an electrical network based on neuron-axon-dendrite-neurotransmitter connections, that even when we had the evidence, it was hard to grasp the idea that the ligand-receptor system represented a second nervous system, one that operated on a much longer time scale, over much greater distances. The nerves were the classical subject of neuroscience, the route science had taken in its first explorations of the brain and central nervous system, so it was only with some disgruntlement that people could contemplate the idea of a second nervous system. Especially difficult to accept was that this chemical-based system was one indisputably more ancient and far more basic to the organism. There were peptides such as endorphins, for instance, being made inside cells long before there were dendrites, axons, or even neurons -- in fact, before there were brains.
Until the brain peptides were brought into focus by the discoveries of the 1970s, most of our attention had been directed toward neurotransmitters and the jump they made from one neuron to another, across the little moat known as the synaptic cleft. The neurotransmitters seemed to carry very basic messages, either "on" or "off," referring to whether the receiving cell discharges electricity or not. The peptides, on the other hand, while they sometimes act like neurotransmitters, swimming across the synaptic cleft, are much more likely to move through extracellular space, swept along in the blood and cerebrospinal fluid, traveling long distances and causing complex and fundamental changes in the cells whose receptors they lock onto.
This, then, was as much as we understood about the receptor and its ligands by 1972, before researchers had actually found a drug receptor, and well before the breakthrough involving the immune system in 1984, which used receptor theory to define a bodywide network of information and to provide a biochemical basis for the emotions. In the wake of discoveries in the 1980s, these receptors and their ligands have come to be seen as "information molecules" -- the basic units of a language used by cells throughout the Organism to communicate across systems such as the endocrine, neurological, gastrointestinal, and even the immune system. Overall, the musical hum of the receptors as they bind to their many ligands, often in the far-flung parts of the organism, creates an integration of structure and function that allows the organism to run smoothly, intelligently. But I'm getting way ahead of my story. Let's take a break from the science and look at how some of these ideas developed historically.
A BRIEF HISTORY OF RECEPTORS
While the idea of the receptor mechanism had originated with pharmacologists in the early twentieth century, many university physiology departments took it up as well because they found it a useful concept to explain the new chemical substances being found in the nervous system -- the neurotransmitters. These chemical communicators, which were secreted across the synapse, or gap between neurons, also functioned in a way that could be understood by the receptor-ligand model, even though biochemistry had yet to develop a way to measure what was happening.
The chemical formula of acetylcholine, the first neurotransmitter to be discovered, was still decades away from being diagrammed when physiologist Otto Loewi did his early neurotransmitter experiments following a dream he had one night! These first experiments, performed in 1921, involved the action of a neurotransmitter on a frog heart. Removed from the frog and placed still beating in a large beaker, the heart slowed down dramatically when Loewi applied juice extracted from the vagal nerve to it. The mysterious "vagusstuff" turned out to be the neurotransmitter acetylcholine. Made by the nerves, acetylcholine causes a slowing of the heartbeat and a rhythmic stimulation of the digestive muscles after eating, which together contribute to the feeling of relaxation. For both of these processes, scientists theorized that there were acetylcholine "receptor sites," some on the heart muscles, others on the digestive tract muscles, and still others on voluntary skeletal muscles, but they couldn't actually demonstrate their existence.
Early-twentieth-century theory became reality in 1972, when Jean-Pierre Changeux addressed a pharmacology conference in England. With a dramatic flourish, the biochemist pulled from his breast pocket a tiny glass tube with a single narrow blue band across its middle. The tube contained pure acetylcholine receptors taken from the body of an electric eel and separated from all the other eel molecules and stained blue. This was the first time a receptor had been isolated in the lab.
Changeux explained how the feat had been made possible by an unholy alliance between a cobra and an electric eel, with the former supplying the venom to isolate the receptors from the latter. In higher animals, the cobra's venom acts by entering a victim's body and diffusing to the acetylcholine receptors, including those on the diaphragm muscles, which regulate breathing. The venom blocks the access of natural acetylcholine to its receptors. Since acetylcholine is the neurotransmitter that's responsible for muscle contraction, the resulting paralysis of the diaphragm muscles causes death by suffocation.
Now, it just so happens that the densest concentration of acetylcholine receptors to be found anywhere is in the electric organ of the electric eel. Scientists had found that snake venom contained a large polypeptide, called alpha-bungero toxin, that bound specifically and irreversibly to the acetylcholine receptors in this organ that supplies the eel's jolt. It literally stuck like glue. By introducing radioactive atoms to the toxin in the snake's venom, Changeux could follow it to where it stuck to the acetylcholine receptors of the eel's electric organ, and thereby isolate those receptors. That is how he had obtained the blue-stained substance in his test tube. The process of making a ligand hot, or radioactive, by introducing radioactive atoms into it was a brilliant innovation, but it was -- and still is -- a very tricky procedure, because the radioactive substance can destroy the ligand's ability to bind, thereby defeating the whole point of the process.
Another major stream that had contributed to "receptorology," as we jokingly dubbed the emerging field, was the discipline of endocrinology, the study of ductless glands and their secretions. Endocrinologists, like the pharmacologists and physiologists before them, needed a way to explain how the chemical substances known as hormones acted at a distance from their sites of release on their targeted organs. But in those days -- we're talking the 1950s and 1960s -- it wasn't very likely that an endocrinologist would be found talking to a pharmacologist. Each field of study occupied its own little niche and was separated from the others by strictly drawn boundaries that defined the disciplines. Those working within a given discipline were generally unaware of and uninterested in what their fellow scientists were doing elsewhere. So people in each field kept making parallel discoveries without understanding what these discoveries had in common.
In the 1960s, endocrinologist Robert Jensen had been able to use a microscope to see estrogen receptors that had bound with radioactive estrogen he'd injected into female animals. As predicted, the radioactive estrogen went to receptors in breast, uterine, and ovarian tissue -- all the known target organs for this female hormone. Later, estrogen receptors, as well as receptors for testosterone and progesterone, were unexpectedly found in another organ, the brain, with amazing consequences for sexual identity. But that's a later part of our story.
In 1970, endocrinologists Jesse Roth and Pedro Cuatrecasas, working on separate teams at the National Institutes of Health, were able to measure the insulin receptor by following Changeux's approach of rendering their ligand -- insulin -- radioactive. Before, Cuatrecasas had been able to get close enough to show that insulin receptors were located on the outside surface of cells. But the new techniques for labeling substances with radioactive atoms were among the key advances that allowed for the actual measurement of the receptor, a tremendous breakthrough in this field.
A NEW IDEA
My own work in "receptorology" began in 1970, in the halls of the pharmacology department of Johns Hopkins University, where I was able to earn my doctoral degree studying under two of the world's experts on insulin receptors and brain biochemistry. At that time, the insulin receptor was the only receptor being studied with the new methods that had been developed for trapping the more slippery ligands, that is, those that, unlike the snake toxin when it bound to the acetylcholine receptor, did not stay irreversibly stuck to its receptors. No one had tried the new methods on any other drugs. But there was clearly a need to study other receptors to try to trap other kinds of ligands.
In my own field, for example, the prevailing dogma was, as I mentioned earlier, that no drug could act unless fixed. This presented an interesting challenge to neuropharmacology, the particular area of pharmacology in which I had become interested, because, theoretically, it meant that if a drug worked, there had to be a receptor, and our job should be to find it. The drugs we were studying at the time were drugs that obviously changed behavior -- I almost said consciousness, but back then nobody used the C-word, except the hippies. Yet everyone recognized that these drugs, which included heroin, marijuana, Librium, and PCP ("angel dust"), precipitated a radical change in the emotional state, that is, altered the state of consciousness of those who used them. That's why, when I began my career in the early 1970s, such drugs were our main tool for studying the chemistry of the brain.
The problem was that our drugs were all from plants, and it was well known that once in the body these plant-derived ligands bound to receptors so briefly before exiting the body in the urine that they were difficult, if not impossible, to catch and measure on their receptors.
The challenge I would eventually make my own was to use the new methodology to trap the small morphine molecule on its receptor in a test tube -- a receptor that many people didn't even believe existed. The proof that it did would have ramifications beyond my wildest dreams. In completely unexpected ways, the discovery of the opiate receptor would extend into every field of medicine, uniting endocrinology, neurophysiology, and immunology, and fueling a synthesis of behavior, psychology, and biology. It was a discovery that touched off a revolution, a revolution that had been quietly under way for some time -- about which more will be revealed in the future lecture sections in this book. But now my own story must begin.
One warm summer afternoon, shortly after I had been accepted into graduate school at Johns Hopkins University, I was packing for the move to Edgewood, Maryland, where I would live with my husband, Agu Pert, and our small son, Evan. As the material objects of domestic life -- the dishes, the clothes, the iron I'd used to iron Agu's white shirts -- began to disappear into boxes, I became aware of a growing sense of panic. By the time Agu came home, I was immobilized, slumped in a chair and fighting back tears.
"What's with you?" he asked, not taking much notice of my disturbed state. Always the calm and steady one, he said nonchalantly, "It looks like you got a lot done."
"I know," I responded, trying to rally myself. "But graduate school...graduate school...it's an hour away. How will I ever..." I trailed off, overwhelmed by the thought of the challenges that lay ahead of me. How would I balance the chores of my role as wife and mother with the demands of earning a Ph.D. degree, commuting daily to Baltimore, and working full-time in a laboratory? I gestured pathetically at the boxes on the floor.
"Don't worry," Agu declared. "I'll do it all! I'll do the cooking, the cleaning, I'll make sure Evan gets to day care. Your job is to concentrate on going to school and learning psychopharmacology."
And that's exactly what I did.
Copyright © 1997 by Candace B. Pert
