by Greg Gibson
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
1. The adolescent genome
genetic imperfection Disease is a normal and inevitable part of life that arises from the way that organisms are put together.
unselfish genes The way that different flavors (alleles) of thousands of genes work together establishes how an organism looks or behaves, or how healthy it is.
how genes work and why they come in different flavors We all differ from one another at millions of places in the genome.
three reasons why genes might make us sick Rare alleles that have a large impact, common alleles that have a moderate one, or hundreds of alleles with very small effects can all contribute.
a unified theory of complex disease The combination of rapid human evolution and recent cultural change has pushed us out of a genetic comfort zone, predisposing many more people to disease.
the human genome project Public and private efforts have jointly produced a complete sequence of the human genome that lays the foundation for a century of medical research to come.
genomewide association The scalpel that will be used to isolate most of the major disease susceptibility alleles for complex disease of the next few decades.
Genetic Imperfection
Of all the paradoxes in the world, surely one of the most absurd is that the very same genome that gives us life inevitably also takes it away. Even when they aren’t killing us, our genes are generally making existence more difficult than seems absolutely necessary. Very few people escape this world having avoided a bout with cancer or diabetes or asthma or depression, and those who do often end up too senile to remember much of the journey anyway. What good reason could there possibly be for so much suffering and disease?
Maybe there is no good reason, other than that genetic disease is an unavoidable byproduct of the way organisms are assembled; disease arises because humans, like all other species on the planet, are an unfinished symphony. Perhaps we are even more unfinished than most, thoroughly out of equilibrium with the modern world, and even a little bit uncomfortable in our own skin. In short, we possess an adolescent genome.
This notion may seem counterintuitive, because we are so conditioned to think in terms of perfection. A simplistic way to think about biology is to imagine that every species is perfectly suited to whatever ecological niche it occupies. Its genome has evolved to ensure that each individual is made to be as close as possible to the optimum shape and set of functions that a perfect member of the species would have. Adaptation to a dragonfly is having exquisitely refined lace wings, to an orchid it is pitching the lips of its pouting petals at just the most attractive angle, and to a human it is whatever it takes to live a long and comfortable life. Maybe no one individual is ever truly cast as the ideal that defines the species, but all approximate the optimum.
If an individual doesn’t quite define perfection, it is either because optimality actually comes in a variety of shapes and sizes, or because forces are conspiring against the person. Debating whether humanity is more closely realized in the form of Colin Powell or Tiger Woods, Jennifer Lopez or Hillary Clinton, we would no doubt agree to disagree on what attributes are desirable in a person. We would, however, likely find common ground when it comes to health, concluding that some not-so-optimal types of genes floating around make us hypersensitive to pollen, push us to eat too much, or make us prone to mental illness. So the question is, why are such bad influences tolerated in the gene pool?
As the book unfolds, we will look closely at six different types of disease, each given i
ts own chapter. It is first necessary to lay the foundation, so I have three goals in this opening chapter: first, to disavow you of any sense that there is such a thing as a “disease gene;” second, to lay out the general theory of complex disease that I enunciate as the book unfolds; and third, to explain how contemporary geneticists go about finding the genes that influence susceptibility to illness.
Unselfish Genes
Telling someone that she has the gene for Parkinson’s or the gene for restless leg syndrome is a bit like telling her that her house has termites or sits on a toxic dump. It implies that her misfortune is that she has something that most people don’t have, and further that all would be well if only she could get rid of the termites or toxins.
Genes are not like that, though. They are not things that some people have, and others do not. Approximately 23,000 genes are in the human genome, and all of us have pretty much the same number, give or take a few dozen. What we actually have are different flavors of genes. The technical term for a gene flavor is allele, pronounced ah-lee-el: Whenever you read the word “allele,” think of chocolate and vanilla ice cream. Alleles are different versions of the same gene, just with different spelling and slightly different function.
In fact, in many cases, when a gene is associated with a disease it is because the gene is in some way broken or missing. Just getting rid of the gene would not help. A better house analogy than termites and toxins might be damp foundations, or cheap window frames. The house is basically the same as everyone else’s, but problems arise because it just wasn’t built as well as it should have been. Generally in such cases, many other things also are likely to go wrong and in this sense, too, the analogy with complex disease is improved.
Similarly, it seems that almost daily we read proclamations that scientists have discovered the gene for stroke or the gene for homosexuality. In almost every case, what they really mean is that the scientists have discovered a particular variant of a gene that slightly increases the likelihood that some people will suffer strokes or prefer their own sex. Sometimes the headlines replace “the” with “a,” which is definitely better but still conveys the impression that the purpose of such genes is to cause the disease or trait. Actually, the genes universally promote what we colloquially refer to as normality. They come in different alleles, and under some conditions particular alleles promote disease, or conditions we choose to label abnormal.
Contemporary genetic research is focused on finding these alleles and is as much about basic understanding of what they do as it is about finding cures for specific diseases. This is because there is little prospect of finding new cures for cancer until we understand why tumor cells grow out of control in the first place, and the next drugs for treatment of depression won’t arrive until we appreciate what is wrong deep inside the brains of the chronically sad. This makes sense if you consider that most of us would prefer that our automobile mechanic understand how the engine works, rather than just try the same old fixes he’s always used in the past.
The advantage that a mechanic has is that humans made cars, so we know not just what every part does but also what its purpose is and how it interacts with all the other parts. Biomedical researchers now have a pretty complete parts list and a fair idea of where each part goes, but there is still much to be learned before we know what all the parts do and how they fit together to make a healthy person.
Much genetic research involves pulling apart and putting back together model organisms that we can manipulate, like mice and rats and zebrafish, and even flies and nematodes. Increasingly the tools are at hand to do it with humans directly—at least, the pulling apart bit. Also, for just about every gene, somewhere in the world there is a person with an allele that does not work, and many thousands of these are responsible for rare syndromes. They are teaching us a lot about how things function, but for the most part don’t explain the common diseases that afflict us all.
To this end, a parallel mode of genetic analysis is much less familiar to most people and yet influences all of our lives on a daily basis to a much greater extent than the genetics that we learn in school. Variously referred to as quantitative genetics, or by phrases such as complex disease, multifactorial trait, or polygenic disorder, it is the study of how common variants in many genes interact with one another and with the environment to produce the biological variation that surrounds us. Genes are fundamentally interactive entities, working together, adjusting to the environment around them, molding organisms but not determining their destiny. For anything the least bit complicated, it truly takes a genome.
Most of the differences between species are of this type, as are the attributes that make us unique, from body shape and facial features to metabolism and even aspects of temperament. So too are the diseases that touch every one of us directly or indirectly as they afflict friends and family: cancer, diabetes, cardiovascular disease, asthma, and depression. The language associated with quantitative genetics switches from the imagery of control, determination, and causation, terms popularly associated with genetics, to the less strident tones of susceptibility, influence, and contribution. This book is predominately about the genetics of complexity.
Perhaps another analogy might make the distinction clearer. All of us are probably painfully aware of the impact that one individual can have on a business. If the CEO, or CFO, or CSO, or Director of IT, or head housekeeper for that matter, stops working or starts making bad decisions, the company can deteriorate rapidly. Yet it is the more subtle failings or distractions of multiple employees that most often disturb the health of the company even in good times. Two co-workers are going through a divorce, a supervisor is having an affair, the junior VP for marketing is caring for her ailing mother, and one of the bookkeepers has repetitive strain injury. Nothing is particularly unusual about any of these circumstances, and each of them is almost to be expected in even a moderate-sized group of people. For the most part organizations can and do deal with them, but mix them together in certain combinations and pretty soon potential dissipates, opportunities are lost, maybe employees start leaving, and things can fall apart. Such is also the fate of our genomes: Genes are ultimately individuals that have to work together, but they’re not perfect, and sometimes the pieces just don’t mesh.
Far from being selfish robots, genes are in fact little molecular existentialists. Contemporary molecular biology is about relationships and networks. It is the context within which a gene is used that defines what it does and what it is. Sure, certain genes are essential for the development of the eye or the heart, but these same genes do other things in different contexts. Think not of genes as dictators, but rather as a parliament of constituents—a parliament that on the whole does a pretty decent job, but sometimes messes up, with dire consequences for the health of the organism.
How Genes Work and Why they Come in Different Flavors
Even if you haven’t asked yourself why it is that genes makes us sick, perhaps you have wondered why it is that your sister has legs up to her ears and piercing blue eyes that haven’t been seen in the family since Great-Aunt Bessie, while you seem to have inherited a horrible mix of dad’s stockiness and mom’s frumpiness? And what’s up with your brother’s moroseness: Where did that come from?
It is not much of an explanation, but the straight answer is that genetics is a lot more complex than the idea that there’s a gene for every trait. Most traits, or attributes, are regulated by many genes, not just one. Furthermore, while it is a nice abstraction to suppose that genes come in normal, or good, versions and mutant, or bad, ones, the reality is that there are always multiple different flavors of normal. The gradation from the most common allele to various types of normal alleles to abnormality is continuous. Just having certain alleles is insufficient to predict whether a person will get a disease.
Crucially, too, the environment has a pervasive effect on the way our genes function. “Environment” means much more than the temperature outside or the nutritional
content of the food we eat. It also includes influences as diverse as a mother’s health during pregnancy and the pressure that peers and society put on us to behave in certain ways. As we shall see, in many cases environmental interventions are likely to have a much greater impact on public health than pharmaceutical ones. Unfortunately, most of us find it easier to pop a pill than to buck a social trend, so drugs are likely to have an ever-increasing role in disease control.
Without going into any mechanistic details, it is helpful to recognize that genes function on two levels, the biochemical and the biological. The biochemical is hidden to most observers, and therefore typically excluded from general conversation. The biological is what we actually see.