by Greg Gibson
It Takes a Genome
How a Clash Between Our Genes and Modern Life Is Making Us Sick
Greg Gibson
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Printed in the United States of America
First Printing January 2009
ISBN-10: 0-13-713746-X
ISBN-13: 978-0-13-713746-6
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Dedication
For Diana
Contents
Preface: How a genetic culture clash with modern life is making us sick
Chapter 1: The adolescent genome
Chapter 2: Breast cancer’s broken genes
Chapter 3: Not so thrifty diabetes genes
Chapter 4: Unhealthy hygiene
Chapter 5: Genetic AIDS
Chapter 6: Generating depression
Chapter 7: The alzheimer’s generation
Chapter 8: Genetic normality
Notes
About the author
Index
Praise for It Takes a Genome
“A compelling, witty, and reader-friendly explanation of how our genes, fashioned for living in the Stone Age, are not so well-suited to life in the Modern Age.”
—Sean B. Carroll, author of The Making of the Fittest and Remarkable Creatures
“It’s taken thirty years, but we finally have in Greg Gibson’s It Takes a Genome what is truly a biologist’s response to the single-gene focus of Richard Dawkin’s early classic The Selfish Gene. And what a response it is! In Gibson’s world, we see a genome as an integrated whole, making sense only when the constituent parts, the genes, are considered in their full genomic and environmental context. It is an engaging, fascinating, accessible, and ultimately deeply satisfying perspective that will enrich the way we all think about ourselves and how we got to be the way we are.”
—David B. Goldstein, Professor of Molecular Genetics, Duke University
“Gibson has captured the delicate balance between the excitement of the genomic revolution and the frustration that so much is yet to be learned about the genomics of disease. This book is an ideal guide through the complexities of recent environmental change and how this non-genetic process has interacted with human genomic variation to produce today’s landscape of important chronic diseases.”
—Marc Feldman, Professor of Biology, Stanford University
“Gibson deftly synthesizes the new science linking genome variation and human health, debunking entrenched views about the causes and evolution of disease and arguing convincingly for a more comprehensive view. An important book and a great read.”
—David P. Mindell, Dean of Science, California Academy of Sciences
“Geneticist Gibson is a natural teacher. He brings a welcome balance to his descriptions of the roles of genes, the environment, and chance in the major human diseases.”
—Bruce Weir, Chair and Professor of Biostatistics, University of Washington
Preface: How a genetic culture clash with modern life is making us sick
We humans, I am sure I have little need to convince you, are an extraordinary species. Whether you regard us as the pinnacle of Creation or the latest exemplar of the evolutionary process, our genes endow us with a certain uniqueness. We are capable of great athleticism, artistic genius, bravery, brilliance, creativity, and conscious reflection. No other species has our linguistic dexterity, or the reasoning skills that have led us in a few short millennia to dominate the planet. Yet for all this wonder, we are also astonishingly genetically vulnerable. More than half of us will die of a complex disease whose origins can be traced to genetic susceptibilities that place us at risk in the modern environment of our making.
The seeds of our discontent lie hidden in the human genome, uncovered now by a genetic culture clash with contemporary life. It turns out that organisms evolve not just to approach some optimum, but also to be buffered against the vagaries of circumstance. Take any species outside its comfort zone, and all of a sudden it gets a whole lot more vulnerable. In the last few hundred years, humans have created an environment defined by fast and sugary foods and bland immune exposure, while our mental world is shaped more by electronic energy than the soft sensibilities of the biosphere. Is it any wonder that diabetes, asthma, and depression are almost epidemic?
The mission of this book is to explain how our genes make us sick. Secondarily, it is to advance the thesis that they do so in large part because the genome is out of equilibrium, with itself and with the environment. If you like, our genes are “not in a happy place.” So much has changed so quickly in human history, starting 10,000 generations ago with the origin of the species and accelerating 10 decades ago with the pace of industrialization, that many genetic processes are not quite right. The stress of modernity provides a little extra shove that pushes otherwise perfectly normal varieties of genes to the brink of malfunction. Like a bad casserole, some flavors just don’t go together, certainly not with the ingredients they are being paired with. Flavors that throughout primate history have been perfectly innocuous now find themselves singled out as the bad guys, as the risk factors that contribute to obesity and inflamed bowels and kids who can’t pay attention.
All I ask of you is to suspend some of the beliefs that you may have picked up from the media, or from fundamentalist Darwinians. It is convenient for journalists to write stories about genes for this or for that: genes for aggression and genes for altruism; good genes and selfish genes. But it is the way that genes work together inside cells that influences whether your nose is long or your girth is rotund. Every single gene comes in a variety of types, some common and s
ome more rare, and just about every gene has multiple tasks and responsibilities. The key to understanding why they make us sick is to understand that, just like every one of us, they are just trying to do their best given the features they were endowed with in a complicated world. With the best intentions, sometimes things just don’t work out—particularly when we’re outside our comfort zone.
This book is written from the perspective of an empirical evolutionary quantitative geneticist. A what? This is actually a mainstream branch of biological research, one populated by several faculty members on most university campuses from New York City to Manhattan, Kansas, and that underlies an increasing volume of the genetics you read about. The “quantitative” part is a code word for concepts such as complex and diverse and statistical estimation. It is the genetics you never learn in high school but certainly should, because it is the genetics of everything we encounter on a daily basis. Height, color, degree of spirituality, and disease susceptibility all have tendencies to be transmitted from parent to child, and all are influenced by many genes interacting with the environment. The Human Genome Project has brought the study of these interactions to our fingertips, and much of what I have to say is about this new learning.
The “evolutionary” part is a nod to history, recognition that we are a product of our past. We can certainly study genetics with a singular focus on the here and now, possibly going back just a generation or two, but everything makes so much more sense when we see things in the context of millions, and even hundreds of millions, of years of life on Earth. Nary a serious practicing research geneticist does not embrace the facts and theory of evolution. The core theory is actually due to twentieth century luminaries such as R. A. Fisher, J. B. S. Haldane, Sewall Wright, Richard Lewontin, and Motoo Kimura, who built genetics into the edifice founded by the grand old Victorian Charles Darwin. There are, of course, lively debates about the details of the process, but there is little disagreement with the realization that the inclusion of history helps us understand how things work. The past has shaped the present just as much in our genes as in our beings.
The “empirical” part places the emphasis on observation and experimentation. Theory plays a crucial role, but alone it can be horribly misleading. Certain aspects of theoretical genetics have garnered popular attention, most notably the more rabid strains of sociobiology that equate human behavior with the lekking of a bowerbird or the castes of a honeybee. Yet it is only by getting our hands dirty with real data can we sort the actual from the possible. Reams and reams of data are now at hand, generated by automated DNA sequencers that churn out millions of bits of information every second in high-tech genetic power plants that have popped up like mushrooms across our campuses. A scientific revolution is in progress, and this too is the subject of the book.
We will follow an orthodox strategy. The six core chapters deal with each of six major classes of human disease sequentially: cancer followed by diabetes, inflammatory and infectious diseases, and then two domains of psychology, depression and senility. These six chapters are sandwiched between an introduction that lays the conceptual foundation and a conclusion that offers some thoughts on human diversity more generally.
Chapter 1, “The Adolescent Genome,” explains how genes are for the most part extraordinarily interactive and cooperative entities—“it takes a genome” to build most traits. We’ll consider the notion of molecular existentialism, which is a way of saying that what a gene does is very much a function of whom it knows and whom it works with on a daily basis. Here one gene affects the hardness of your tooth enamel, there the growth of your cranial nerves, and elsewhere it helps to ensure that your liver is the right size. It does not make much sense to talk about a gene for eyes or a gene for altruism. Rather, we need to think of things in terms of variation. Every single gene comes in a variety of flavors, and whether you are taller or shorter, more or less prone to diabetes, or better at shooting a basketball than the next guy, is influenced by the flavors you get at dozens if not hundreds of genes. They work together in intricate networks that in a sense breathe with the environmental variation as well. Cystic fibrosis and muscular dystrophy aside, this leads to the idea that disease is most often not the result of a single bad gene, but instead is caused because the genome is not yet mature, and there is a mismatch between combinations of normal varieties of gene and unfavorable circumstances.
Chapter 2, “Breast Cancer’s Broken Genes,” concentrates on breast cancer. It is a bit of a strange place to begin our survey of the genetics of complex disease, because the way genes cause cancer is very different from the manner in which they influence the other diseases. For one thing, they really cause it. Once the genes inside a cell are broken beyond repair, there is nothing to be done other than to control the damage either by cutting out the tumor, or destroying it by cutting off the blood supply or actively killing the cells. Certainly a healthy spirit helps, but there is a shocking inevitability about cancer. For another, it is not the genes we get from our parents that matter, for the most part, but rather the things that happen to them during our lives. Genes break, just as faucets and gutters and washing machines and radiators break in the course of wear and tear. They come with a warranty in the form of an active toolkit for repairs, but when the repairmen themselves break down, trouble really sets in, most notably in breast and colon cancer. Cancers take multiple mutations to get started, and each of us inherits a set of mutations whose effects are veiled by the rest of the healthy genome, only to exert their effects as other mutations accumulate. Nor are there really cancer genes, in the sense that there are not genes whose role it is to promote cancer: What we call cancer genes are just normal, for the most part essential, genes that we need for normal growth and development, and when these are broken, they lead to cancer. Importantly too, it needs to be emphasized that much of the recent increase in cancer rates has been brought on by human activities—some that we don’t want to do much about, such as growing older and maturing earlier, and some that we can control, such as avoiding smoking or sunbathing all day. In the end, cancer is as much about genes interacting with the modern environment as any other disease.
In Chapter 3, “Not So Thrifty Diabetes Genes,” our attention turns to diabetes. One type of diabetes is due to immunological problems, but the predominant type is allied with obesity. We know now that obesity and type 2 diabetes are joined with cardiovascular disease and stroke in a spectrum of discomfort known as metabolic syndrome that affects almost a third of all westerners. These diseases all trace in part to the incapacity of our genes to cope with contemporary lifestyles. The title is a play on a popular hypothesis in evolutionary medicine that disease emerges as a result of conflict between selection in the past and the needs of the present. Supposedly, genes that helped us survive famine by rapidly storing fat now promote diabetes by slowly accumulating it in excess. However, the data really don’t support this, and instead I develop the concept of disequilibrium between veiled variation that in the past had little or no effect on human physiology and the energy dense diet of our times. In fact, metabolic syndromes are the poster child for genetics in the era of genome biology, as the application of brute-force screening has revealed the identity of dozens of risk factors. Something called the common disease-common variant hypothesis seems to hold true. Diabetes really does trace, in part, to different flavors of genes that perhaps a quarter of us have, and it is the combinations of these common flavors with environmental factors that predicts disease—“predicts” in the sense of epidemiology, not necessarily an individual. Someone with every hedonistic tendency in the world who has even been dealt a sorry deck of genetic cards can nevertheless live long and prosper, while another poor soul who sticks to the Atkins Diet may find him- or herself overweight and encumbered with a failing heart in middle age.
Chapter 4, “Unhealthy Hygiene,” turns to a discussion of inflammatory immune disorders. There’s a litany of A’s: asthma, atopy, allergies, and arthritis, in addition t
o the autoimmunity of inflammatory bowel disease, lupus, and multiple sclerosis. Here the story is one of shifting balances. Our immune systems are set up to protect us against three classes of enemies—viruses, bacteria, and parasites—while avoiding the perils of friendly fire. They operate in a constantly changing battlefield and deploy constantly against shifting artillery. Moreover, the nature of the threat has changed a couple of times in human history, first with the increased exposure to zoonotic disease, as we adopted pets and domesticated livestock; and more recently as we moved into crowded cities and/or sterile suburbs. As much as one-fifth of our genome is set up to help us cope with pathogens, operating in a complex web of interactions full of checks and balances. The challenge of our time is not to overreact to perceived threats without doing more harm than good, but the confusion in our genome, pushed to the edge of its buffering capacity, emerges in the form of inflammation and irritation.
A short Chapter 5, “Genetic AIDS,” is reserved for the other side of immune malfunction, the Human Immunodeficiency Virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS). This disease is a lightning rod for discussion of so many of the deep moral concerns of humanity, bridging notions of individual responsibility (for behaviors that often lead to infection) to the burden of care of the developed world to the developing world (while respecting local governmental autonomy). We will see that widespread variation in our genes determines who will be protected and who will be able to cope with chronic infection, and we will see that this variation is unevenly distributed among different ethnicities. Further, it seems that some of the protection can be attributed to past episodes of response to bygone plagues and epidemics.
The focus shifts to behavior in Chapter 6, “Generating Depression,” which is all about psychological diseases. Profound sadness and anxiety may yet join diabetes as the defining discomforts of the twenty-first century. Alcoholism and other addictions of abuse blight the lives of those unfortunate enough to suffer the pain they cause, as do the health policies of societies that refuse to acknowledge that the capacity for self-control is not equally distributed. No one can seriously doubt any longer that genes contribute to psychological maladies, but, unfortunately, geneticists cannot yet see a coherent picture of their role. Perhaps thousands of rare mutations contribute, or perhaps here is where the misfit between our genomic heritage and contemporary life is at its starkest. Kids these days learn their way around an Xbox or a PlayStation before they can tell an oak from an elm, or a cirrus from a cumulus cloud wafting across the skies. Every aspect of our mental world, be it relationships, careers, or pastimes, is new, and we careen through life at a pace that we just did not evolve for. Surely the pressures on the nervous system are at least as great as those on our metabolism and immune systems, so here too disease emerges from the unveiling of normal variation under the stress of modernity.