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 some 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 to 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.

The final core chapter, Chapter 7, “The Alzheimer’s Generation,” is appropriately placed at the end of our survey of genetic discomfort and deals with senility and growing old. This chapter recognizes that every adult becomes conscious of the dementias in their middle age when their thoughts turn to care of aging loved-ones. There’s plenty of evolutionary theory about conflicts between genes that are good for us when we’re young but turn against us as we age, or about genes not caring so much about keeping us alive after we’ve raised our offspring. However, some of us are predisposed genetically to decay mentally at an accelerated rate, and modern genomics tells this one last story of disequilibrium between our genetic past and contemporary lifestyle.

I need to emphasize that despite all this, I am not advocating a turning back of the clock or a return to some lost utopia that never was. To use a well-worn phrase, modernity “is what it is.” It is unrealistic to expect people to undo the cultural changes that have placed all this pressure on our genomes, but it is realistic to hope that we can come to a better understanding of how our genes interact with one another and the environment. This is not a book about prescriptions. For all the anguish in our lives, arguably humans have never experienced as much happiness as they do today. For all the discomfort of old and middle age, we live longer and have immeasurably more comfortable lives than ever before. This book is fundamentally an attempt to address an imbalance in the way that nature and nurture are presented as one-or-the-other causes of disease. Every publication of a gene for cancer or a gene for diabetes or a gene for aggression raises expectations for a fix, be it genetic manipulation, or a simple over-the-counter drug; some might even desire a eugenic breeding program. No, genes are not instructions engraved in the tablet of our DNA determining this or that. They are just sequences of letters that orchestrate tendencies, and we ought to embrace their variety.

This is the idea we return to in Chapter 8, “Genetic Normality.” Why is it that some people are tall and some short; some are dark-skinned and others fair; some people (and even some Vice-Presidents) seem to have a permanent scowl while others have bright, welcoming smiles? There is ample variation for the dimensions of psychology, such that some of us are introverted yet open to new ideas, some are conscientious and emotionally stable, and others are disagreeable. Little is known about the genetics of such attributes, other than that they do run in families, so it is really only a matter of time before we begin to find the genes. Already, though, we can be sure that they will tell a story much like those related to disease, a story of complexity and of interactions.

Normality is a distribution, not a category. Distributions have extremes, and those extremes are as much a part of life as the fact that most individuals occupy the middle. Every single one of us is extreme for some human attribute, because we inevitably have some unique constitution of genetic variation. To be human is to participate in the extraordinary diversity of flavors in the human gene pool, a diversity that may be responsible for illness and frailty but deserves equal credit for human creativity, beauty, and accomplishment.

The ideas in this book have incubated over a period of 15 years, and I would like to collectively thank and acknowledge all of the many colleagues who have encouraged, supported, and criticized along the way. Of course that particularly means everyone in my research group, whom I owe more gratitude than I can express. A few people have been particularly important over the past year or two: Karl Leif Bates and Beth Weir read drafts of most chapters early on and provided me with the confidence to continue, while David Goldstein was also a rock of encouragement at a critical juncture. Their task was made easier by the fact that a wonderful puppy named Razzie got me out of bed for walks and morning writing sessions. Amanda Moran and Tim Moore at Pearson have taken a punt on the book, and I cannot thank them enough for that and for allowing me to be part of the new science imprint at FT Press. Russ Hall has been the perfect editor for me; any deficit in his powers of persuasion is simply a product of the fact that my own degree of stubbornness is highly canalized. The book covers a huge space of biomedical literature, and since I mainly study flies rather than specific diseases, it is inevitable that errors of fact and interpretation have crept in: Responsibility for these is completely mine. I hope that the overall message nevertheless seeps through. Finally, because she is my antidote to all the complexity in the world, I dedicate this book to my wife, Diana.

Greg Gibson
Raleigh, December 2007