Preface

What Your Genes Are Wearing

HERE’S A PUZZLE. CONSIDER THE CASE OF TWO BROTHERS, when each had reached the age of twenty. One of them—call him Al—was a typical young male. His brother, Bo, however, was not at all typical of young males at this age. Bo looked more like a preadolescent male: poorly developed muscles, absolutely no facial hair, and a voice to match. Their mother was understandably worried about Bo, and soon after his twentieth birthday finally convinced him to see a doctor. Once Bo removed his clothes, the doctor immediately noticed that something was missing—his genitals. A closer inspection revealed that he did in fact have genitals but nothing like those you would expect of a twenty-year-old male. They seemed vestigial. The doctor’s diagnosis was Kallmann syndrome, a disorder of sexual development.¹ What’s puzzling is this: Al and Bo are identical twins, nature’s clones. So what happened to Bo? And why didn’t it happen to Al?

Kallmann syndrome is an odd-seeming mixture of developmental defects. Not only is sexual development affected, but so too is the sense of smell. Those who suffer from this disorder have greatly impaired olfaction; some have no sense of smell whatsoever. This strange-seeming association reflects the fact that Kallmann syndrome is a developmental defect in a certain part of the embryonic brain called the olfactory placode.² As the name implies, it is from this part of the brain that our olfactory sense develops, but it is also from this part of the brain that certain neurons originate that play a huge role in sexual development. During normal sexual development these neurons migrate from the olfactory placode to the hypothalamus. In those with Kallmann syndrome this migration is disrupted.

It is also noteworthy, therefore, that even though only Bo’s sexual development was impaired, both Al and Bo have an impaired sense of smell; both, in fact, have Kallmann syndrome. Why is Bo’s case so much more severe? Kallmann syndrome is generally considered a genetic disease.³ Yet Al and Bo share whatever genetic defects may have contributed to Bo’s condition. What is it that they don’t share? The story of Al and Bo is based on a real case study,⁴ one of the more dramatic examples of discordance in genetically identical twins. Nature’s clones are far from identical, which is why the term “identical twins” has been replaced by monozygotic twins.⁵ Their discordances sometimes result from essentially random processes at the biochemical level. We are familiar with one form of biochemical randomness, called mutation, which alters the DNA sequence. It is possible but highly unlikely that Bo’s DNA mutated after the fertilized egg split, in which case the twins would be genetically different. It is much more likely that the differences in Al and Bo are epigenetic in nature. The term epigenetic refers to long-term alterations of DNA that don’t involve changes in the DNA sequence itself. Either Al’s DNA was epigenetically altered in a way that meliorated his Kallmann syndrome, or Bo’s DNA was epigenetically altered in a way that exacerbated it.

The naked gene consists of DNA in the form of the famous double helix. The genes in our cells are rarely naked, however. They are, rather, clothed in a variety of other organic molecules that are chemically attached. What makes these chemical attachments important is that they can alter the behavior of the genes to which they are attached; they can cause genes to be more or less active. What makes these attachments even more important is that they can stay attached for long periods of time, sometimes a lifetime. Epigenetics is the study of how these long-lasting, gene-regulating attachments are emplaced and removed.⁶ Sometimes epigenetic attachments and detachments occur more or less at random, like mutations. Often though, epigenetic changes occur in response to our environment, the food we eat, the pollutants to which we are exposed, even our social interactions. Epigenetic processes occur at the interface of our environment and our genes.

Getting back to twins Bo and Al, it is impossible to say whether their differences reflect random or environmentally induced epigenetic differences. Nor can we know, in this particular instance, what genes are involved. It could be the same genes, the mutations of which are implicated in Kallmann syndrome, or the epigenetic differences may occur in altogether different genes that influence sexual development. We need more than one case study to determine these things.

Al and Bo will continue to epigenetically diverge throughout the course of their lives. These epigenetic differences will make Al or Bo more susceptible to Alzheimer’s disease, lupus (systemic lupus erythematosus), and cancer, to name a few ailments.⁷ The epigenetics of cancer is particularly well studied. In cancer cells, many genes lose their normal methyl attachments—they are demethylated. This demethylation results in a host of abnormal gene activities, one consequence of which is unbridled cell proliferation. It is this global demethylation, not any particular mutation, which is the hallmark of cancer. This is good news, because unlike mutations epigenetic changes are reversible. The goal of much medical epigenetics is to find ways to reverse pathological epigenetic events. Many see in epigenetics the potential for a medical revolution.

Another active area of epigenetic research concerns the fetal environment. Al and Bo are less different epigenetically than non-twin brothers because they shared similar environments throughout their lives. This is especially true of the environment they experienced in the womb. Whatever their mother’s diet during that period, it affected them equally. The same goes for whatever stress she experienced during pregnancy. More typical siblings, however, can experience quite different fetal environments. The epigenetic alterations that result will make one or the other more susceptible to obesity, diabetes, heart disease, and atherosclerosis, as well as depression, anxiety, and schizophrenia.

Though the epigenetics of what ails us is the most topical, other sorts of epigenetic processes are, for a biologist, more fundamental. Particularly important is the problem of development: how a fertilized egg can become you or me. The problem of development can be broken out into subproblems. There have been major advances in solving one of these subproblems, called cellular differentiation, because of epigenetic research. We all passed through a stage in which we were a hollow ball of generic cells, called stem cells. These stem cells are not only genetically identical; they are physically indistinguishable as well. How, then, do we come to have skin cells, blood cells, neurons, muscle cells, bone cells, and so forth, all of which remain genetically identical? Epigenetics holds the key to unlocking this mystery.

Epigenetics also informs some mysteries concerning inheritance. Our parents make separate but equal genetic contributions to who we are. They also make separate but unequal epigenetic contributions. For some genes it makes a difference whether you inherit them from your father or your mother. These genes are epigenetically activated if they come by way of your mother, but inactivated if they come by way of your father (and vice versa). Other epigenetic states, some environmentally induced, can be transmitted from grandparent to grandchild.

This book is intended as an introduction to epigenetics for those unfamiliar with this exciting new field of research. It is written for the nonspecialist who seeks to be informed about this important subject. The scope of epigenetics is too vast for a comprehensive treatment, which would be inappropriate for the intended audience in any case. I will cover only some of the highlights and hope thereby to impart a sense of what’s going on.

I have a secondary agenda as well, which concerns the implications of epigenetics. I believe that epigenetics should substantially alter the way we think about genes, what they are and what they do, particularly what they do with respect to our development from a fertilized egg. In the traditional view, genes function as executives that direct the course of our development. In the alternative view, which I advocate, the executive function resides at the cellular level and genes function more like cellular resources. I have tried to present the material in this book so that those uninterested in my secondary agenda will nonetheless learn something of value about epigenetics.

Throughout this book I emphasize research that relates most directly to the human condition, primarily because I believe this is the best way to connect with nonscientists. Humans don’t make great research subjects though, for both ethical and practical reasons. Some of the best epigenetic research is on plants, but I only refer to that work when I cannot find better examples closer to home. I focus, rather, on animal models, and especially mammals. I do not emphasize in the text—as is the norm for many popular science books—specific labs, researchers, or experiments. This is in large part to help the narrative flow. I cover too much ground and the work of too many researchers to make one or a few central to my project. Rather, I want to keep the reader focused on what the research has revealed. The interested reader who wants more information on the researchers and research covered will find it in the Notes.

I have diligently strived to keep the main text as nontechnical as possible. For those interested in more detail, again look to the Notes for each chapter. The epigenetic topics I discuss are covered in a particular order, such that each chapter builds to some extent on the preceding chapters.

Chapter 1 concerns a historical event, the Dutch famine of World War II and its epigenetic consequences. During the course of the next several chapters the reader is provided the tools, in a stepwise manner, for understanding how it is that a famine could influence the long-term health not only of those who experienced it in the womb but of their children as well. First, in Chapter 2, I supply some basic background about genetics that will be essential for understanding epigenetics, including the crucial concept of gene regulation. Chapter 3 concerns garden-variety gene regulation, that is, what was known about gene regulation before we came to understand epigenetic gene regulation. Chapters 4, 5, and 6 delve into epigenetic gene regulation and how it is influenced by the environment, beginning in the womb. In Chapter 7 we turn to the inheritance of epigenetic states, including those induced by the fetal and social environment. At this point we can better understand why the effects of the Dutch famine persist to this day. In the remainder of the book, we move beyond anything that can be gleaned about epigenetics from the Dutch famine example, to explore what are, for biologists, the most significant applications of epigenetics, including stem cells and cancer.