Preface 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, “Keeping Abreast of Cancer,” 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 sunbathi...
