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The Genetic Fuse Box

Autumn 1944: The memory of D-Day burns like a righteous fire in the furnace of the American military, driving the troops on with renewed vigour. Allied forces have made comfortable advances into Western Europe, carving out swaths of mainland and gunning for the heart of the Third Reich. On the Eastern Front, the Soviet war machine trundles inexorably westward, fueled by an endless stream of soldiers and a slow-burning anger at Germany’s betrayal. Things look bad for the Axis. Their westernmost holding, the Netherlands, seems next in line to fall. The Dutch are mutinous and the Allies are closing in. In a fit of desperation and petulance, the Germans cut off the food supply to the western half of the Netherlands and flood the fields, ruining the remains of what was already a subpar crop. American attempts to ship in supplies by barge fail, as winter has set in early and the canals have frozen solid. The Dutch, sealed off on all fronts and left with dwindling food supplies, face the harshest famine in their recent history.

Wait. This sounds familiar, doesn’t it? We described the Dutch Hunger Winter in chapter 3. As you may recall, the effects of the famine did not dissipate in the spring, when the embargo was lifted and the canals unfroze. They reverberated throughout the generations, affecting the children and even the grandchildren of those who had experienced the famine firsthand. Women pregnant during the famine gave birth to children predisposed to heart disease, breast cancer, and obesity. And these conditions didn’t just appear randomly in the affected cohort. Each one correlated to a set of distinct variables, particularly the gender of the child and how far along they were in their gestation when food supplies hit their nadir.

When we first mentioned the Dutch Hunger Winter, it was to illustrate how the environment influences child development in a manner once considered the sole dominion of genes. But we didn’t tell you how the environment went about exerting this influence. We touched on some relatively crude mechanisms, such as how our surroundings provide the basic materials genes need to build their protein products — you may recall the example of hair colour being determined in part by the body’s supply of copper — and attachment theory covers the development of less tangible traits, such as personality or behaviours. But obesity and heart disease aren’t behavioural conditions accounted for by neural plasticity. Nor can the environment’s influence over them be explained away by simple molecular supply and demand. Something more complicated is at play here, something that accounted for environmental conditions (food scarcity) and instructed the fetus to adjust accordingly (store energy in fat cells at an above-average rate). This kind of complex physiological action is generally the purview of genes, but genes aren’t that proactive. They can’t deliberately adapt to abrupt changes in the environmental landscape — at least, not on their own. Perhaps the gene for nutritional thriftiness exists in all of us, but remains to varying degrees inactive, waiting for some outside influence to crank up production. That outside influence is what epigenetics is all about.

Spool and Thread

Picture a strand of DNA in your mind’s eye. Chances are you conjured up, without much effort, an image of two thin ribbons spiralling around one another in the famous double helix pattern, the twin strands connected at regular intervals by nucleotide bonds like rungs on a twisted ladder. This picture is not fundamentally wrong, but it lacks some key details. When not being transcribed, DNA wraps itself around proteins called histones, which cluster tightly together in groups of eight called nucleosomes. Nucleosomes congregate in a squat, highly dense material called chromatin, which, as its name suggests, forms chromosomes.

Think of histones as spools and DNA as the string wound around them. Without these genetic spools, DNA would drift through our cells like giant hairballs, bulgy and tangled and constantly snagging on every protruding protein edge, leaving our genes tattered and ripe for mutation. Histones keep our DNA organized and protected. They also help control the frequency at which our genes code.[27]

When a gene is ready to be transcribed, its portion of DNA unravels itself from the histone, allowing access to the double helix strand. At all other times, our DNA remains neatly wrapped around its histone spools. By adjusting their grip, so to speak, on the DNA spooled around them, histones control how often the genes it protects are available for transcription. And the tightness of their grip is determined by a loose array of proteins and molecules called epigenetic tags.[28]

Nor are histones the only part of our chromosomes controlled by epigenetics. Various molecular hangers-on festoon the outer edge of our DNA, manipulating our genes’ behaviour. Among the most common of these interlopers are a series of alkane molecules called methyl tags. Comprised of carbon and hydrogen, methyl tags latch onto our DNA, annexing the associated gene and discouraging it from coding. The more methyl molecules present, the less inclined the affected gene is to be transcribed. In this sense, methyl molecules act as a dimmer switch, their presence lowering a gene’s activity and, if attached in sufficient numbers, shutting it down entirely.

Methylation, unlike genetic mutation, is completely reversible. A methylated gene will, if unmethylated, resume operating as if it had never stopped working in the first place. However, just because methylation is not necessarily permanent doesn’t mean that its influence on genes is fleeting. Methyl tags can stick with us for years, stowing away during cell replication and remaining in place for thousands of cell generations. Many of the methyl tags in your body right now have been there since you were born, and will stay there until you die. Your children will inherit some of them along with the 23 chromosomes with which you provided them (or will provide them, if said children are currently hypothetical).

The idea of methyl molecules latching onto your DNA seems vaguely sinister, like tiny parasites hijacking your genome, but epigenetic marks are not only common, they’re downright essential to life. They can be found in every cell in the human body; are, in fact, the reason we have different cells in the first place.

Each one of us begins life — in the loosest sense of the term — as a single cell called a zygote, which itself came from the fusion of two gametes (or sex cells): one sperm and one egg. Gametes are, in a sense, half cells, in that they possess only 23 of the typical 46 chromosomes present in every other cell in the human body.

Upon formation, the zygote is almost entirely unmethylated, meaning that every gene present in its cells is unfettered and ready to code. This is a very good thing, because the zygote’s cellular offspring will go on to form every part of the human being it is destined to become, and every one of those genes will have its own part to play in the process.

As the zygote divides, it begins to take the shape of a hollow sphere called a blastula. Blastula cells, like the original zygote cells, are unmethylated.[29] Every gene they possess is capable of transcribing its corresponding protein product.[30] Beyond this stage of development, that begins to change. The blastula cells continue to replicate, and eventually form multiple layers, each with a unique cellular destiny. The outermost layer, called the ectoderm, will become skin and nerves; the middle layer, or mesoderm, will become muscle and bone; the inner layer, or endoderm, will become internal organs.

Development continues. The blastula becomes an embryo, which becomes a fetus, which grows and changes until it becomes a being capable of living outside the womb, at which point the mother goes into labour and gives birth to her baby, who in nine short months managed to transform from a single-celled organism into a complex, breathing, crying, nursing bundle of joy. Along the way, junior’s cells didn’t just divide; they specialized. Ectoderm became skin cells and nerve cells and brain cells. Mesoderm became muscle cells and bone cells and blood cells. Endoderm became stomach cells and liver cells and large intestine cells. And that specialization, though vital, comes at a price of flexibility.[31] Once an ectoderm cell becomes a skin cell, that’s it. Every cell it produces, and every cell those cells produce, and so on all down the line, will be a skin cell. It can’t double back and become a blood cell or a brain cell or a muscle cell. Its career path is set for life.

Why do cells submit to such fatalism? Skin cells aren’t missing the requisite genes for becoming blood cells, or brain cells, or any cell you care to name. With a few exceptions — sex cells being the most obvious — every cell you possess contains all the genetic instructions needed to perform any job in the human body. What stops a blood cell from having a mid-life crisis of sorts and switching fields, becoming a skin cell or a liver cell or a neuron? In a word: methylation. By selectively methylating genes, cells can dedicate their finite resources to performing their assigned duties to the best of their ability. Having cells switch careers would not be beneficial to the organism in its entirety, which benefits from a rigid and highly codified division of labour.

Think of each cell in your body as a tiny nanocomputer, and your DNA as the computer’s organic circuit board. The circuit board dictates the myriad processes responsible for keeping you alive, sending commands from the CPU, or nucleus, to the cell’s many components, regulating enzymes and releasing hormones and synthesizing data from your sensory inputs. Attached to this circuitry is a fuse box called the epigenome, a vast array of tiny methyl fuses, each linked to a distinct gene. Trip the switch and the gene falls silent, its current interrupted by a methyl tag. Remove the tag by reinstating the fuse and the gene comes back into play, its semiconductors alight with a fresh thrumming of energy. It doesn’t matter if the fuse was turned off for five minutes or five years; a flick of the switch is all it takes to get things running again. By contrast, rewiring genetic circuitry is cumbersome, dangerous, and permanent, the result of rogue molecules haphazardly soldering wires and scraping down bits of silicon — in short, mutations. Occasionally, by pure serendipity, these changes allow the machine to function more efficiently at its particular task. Far more often they are disruptive and damaging, and tiny molecular technicians must be called in to fix them.

Unlike genetic mutations, which are accidental and unpredictable, epigenetic tags are easy for the body to regulate. They assure that the most useful circuits get sufficient energy and any processes working contrary to the cell’s goal are silenced, streamlining efforts and increasing efficiency.

Tabula Rasa

Epigenetic effects are not always as predictable as those that determine which cells get which job. Some are downright bizarre. Consider the agouti mouse, an animal intent on proving the misnomer inherent in the term “genetically identical.” For though the genotypes of two agouti mice can be indistinguishable down to the last nucleotide, their phenotypes[32] often appear to be anything but. In adulthood, some have grey-brown coats and svelte physiques, while others have yellow coats and great, rotund bellies. The fat and yellow mice not only suffer from decreased mobility, but also from an increased risk of developing diabetes and cancer. The difference between them and their slim counterparts is the agouti gene, identical in both but only active in the fat mice. In the slim mice the agouti gene is highly methylated, keeping it from producing its affiliated protein; in the fat mice the gene is unmethylated and codes freely, accounting for both the affected mouse’s yellow coat and its corpulent frame.

Having discovered this distinction, the obvious question is what causes it? There is no one culprit, though exposing pregnant mice to bisphenol A — a chemical compound found in a number of plastic products, including, alarmingly, baby bottles — has been found to increase the frequency at which their infants are born with their agouti genes unmethylated. The unmethylated agouti mice are more likely to sire offspring whose agouti genes are also unmethylated, compounding the disorder. Happily, this problem has a remarkably easy fix: feeding mothers pellets laced with methyl molecules greatly reduces their offspring’s chance of having an unmethylated agouti gene. What’s more, when mice who have had their agouti gene “fixed” sire children of their own, the next generation retains the correction despite never having been fed the methyl pellets themselves.

Bearing this research in mind, the effects of the Dutch Hunger Winter no longer seem quite so mysterious. As with agouti mice, pregnant women experiencing the famine gave birth to children with an epigenetic predisposition to a number of adverse conditions, including — again, as with agouti mice — obesity, heart disease, and diabetes. And the famine’s effects didn’t stop at that generation. The Hunger Winter study continues to this day, and researchers still find traces of the famine’s impact on the descendants of those who suffered through it.

Unfortunately, one detail the agouti mice and Dutch Hunger Winter studies do not share is a tidy and easily remedied epigenetic cause. There is no agouti-like gene in humans solely responsible for the intergenerational ramifications of famine, no simple solution obtainable through a judicious addition or removal of a few methyl molecules. There are likely a number of genes at play,[33] some which should be methylated but aren’t, and others that shouldn’t be methylated but are. And even if we developed technology capable of tracking down and altering each offending gene and methyl tag, we couldn’t say for sure that “correcting” the problem wouldn’t cause another more serious ailment to appear in a different system or organ. After all, who could’ve guessed that the same gene responsible for producing yellow pigment in mouse hair also leads to chronic obesity?

Ultimately, the findings of the agouti mice and Hunger Winter studies are less about developing a solution and more about reinventing the way we look at the problem. Epigenetics is a new science, but it has undergone a substantial shift within its short lifetime, and studies like the agouti mouse experiment have been at the helm of this change.

According to conventional genetic theory, inheritance consists of 46 chromosomes passed from parents to their child, 23 from mom and 23 from dad. That’s it. Geneticists acknowledge that nurture is important as well, but its work begins after genes have already spent a full nine months doing their thing. Sure, environmental influences are in a broad sense inherited (since mothers teach children who become mothers who then teach their own children, etc.), but such inheritance is subject to a number of conditional clauses and assumptions (children aren’t adopted, parents raise their children in a manner analogous to how they themselves were raised, etc.) that make them inconsistent and unreliable. Genes, say geneticists, are stalwart messengers, grimly striding through the harshest conditions in unwavering pursuit of their goal: passing their vital chromosomal missives on to the next generation. The environment shifts and slides and changes like the weather. Genes are sturdy as stone.

Except that we are garnering more and more evidence that implies this might not be the case. Environmental influences may not be as capricious as once assumed; indeed, they may stick to our genes for generations. And epigenetics provides the glue that holds them in place.

In its earliest incarnation, epigenetics was not expected to adopt that sort of role. Its methyl tags, though vitally important to proper gene expression, were thought to remain only on the genes of the individual, and not be passed along with the rest of their genetic legacy. The zygote, with its absolute cellular potential, was supposed to be a kind of blank state, the dry-erase epigenetic scribblings of previous generations wiped clean, leaving 46 unadulterated chromosomes ready to be methylated again from scratch. Yet somehow epigenetic information is being inherited. To understand how this happens, we need to think of inheritance as more than a molecular transaction.

Umbilical Telegraphs

Unlike with genes, we haven’t yet developed a satisfactory theory as to why and how epigenetic inheritance occurs. We do know, however, that certain epigenetic traits have critical periods where an action or chemical or experience is especially likely to trigger a long-term change in a gene’s methyl pattern. Often, these critical periods can be found early in a person’s life, particularly when they’re still in the womb. During the Hunger Winter, for instance, the gender and gestational period of affected fetuses determined what condition they would be predisposed to as they grew. Women whose mothers experienced famine during the first trimester of their pregnancy were twice as likely as the normal population to develop schizophrenia. For men, having a mother who experienced famine during the first two trimesters of their pregnancy greatly increased their odds of becoming obese; if the famine extended well into the third trimester, they faced the opposite problem, becoming chronically underweight. These conditions were highly gender specific; women showed no spike in obesity, nor did men show an increase in their odds of developing schizophrenia as a result of early exposure to famine.

Things get stranger still. Consider two genetic disorders, Angelman syndrome and Prader-Willi syndrome. On the surface, they don’t seem to have a lot in common. People with Angelman syndrome have severely reduced cognitive function, lacking the ability to say more than a few simple words. Their movement is clumsy and irregular, marked by jerks and tremors. Yet for all the adversity they face, people with Angelman syndrome — informally called “angels” — are almost universally happy. Their faces alight with beatific smiles. Giggles cascade constantly from their lips, often accompanied by a joyous and endearing flapping of their hands. Indeed, it was the grouping of these characteristics — the smiling, angelic features and erratic, jerky movements — that inspired Dr. Harry Angelman’s original name for the disorder: happy puppet syndrome (the name was eventually changed, as it seemed patronizing).

Compared to “angels,” individuals with Prader-Willi syndrome are far less mentally impaired. Their biggest challenge is in the physical realm. Prader-Willi sufferers have insatiable appetites. They also store fat at unusually high rates. By their teenage years, individuals with Prader-Willi syndrome often become morbidly obese, and those who don’t remain highly susceptible to substantial weight gain for their entire lives.

The Angelman and Prader-Willi syndromes could scarcely be more different. Yet both of these conditions are caused by a partial deletion of chromosome 15, meaning a section of the chromosome was either badly damaged prior to conception or was never present in the sperm or egg in the first place. What’s more, the deletion in both cases is not simply on the same chromosome, or overlapping. It is identical. The exact same genetic defect, down to the last missing nucleotide, causes two completely unrelated syndromes. And the allocation of each syndrome is in no way random; it depends solely on which parent supplied the offending chromosome. If inherited from the father, the deletion causes Prader-Willi syndrome; if inherited from the mother, it causes Angelman syndrome.

It’s difficult to articulate to anyone who is not a biologist how big an upset this is to the understanding of genetic inheritance. Imagine learning that water sometimes flows uphill or gravity takes the odd holiday. A chromosome’s lineage wasn’t supposed to matter. Genes were just genes, and they did their job regardless of where they came from. Yet the Angelman and Prader-Willi syndromes, the Dutch Hunger Winter study, and the agouti mouse experiments all suggest that we don’t have nearly as full a grasp on how inheritance works as we once believed. And there’s no reason to believe these examples are isolated phenomena and not part of a larger trend. Hedonistic pursuits once thought to harm only those who participated in them — smoking, drinking alcohol, eschewing sleep for another night out with friends, eating burgers with unsettlingly honest names like “the Artery Clogger” — might actually be worming their way into subsequent generations. The dangers of fetal alcohol syndrome and smoking during pregnancy have thankfully become well-known, but epigenetic inheritance, it seems, can draw from experiences occurring outside that critical nine-month window.

Our intention is not to send you screaming to the nearest monastery for a life of unyielding austerity. Nor are we suggesting that every cheeseburger you eat is going to haunt your children and your children’s children to the seventh generation like some trans-fat-sodden biblical curse. We simply want to emphasize that the science of inheritance is undergoing a sea change. Parents’ actions can hide in their genes, molecular stowaways riding along unbeknownst to the chromosomes carrying them. We don’t yet understand every motive epigenetic influences have for climbing aboard, but we are aware of one particularly prominent cause: stress.