“I grew up in a small forested area, ten miles north of the Arctic Circle,” Bygren explains.
A slender man with gray hair and round glasses, he walks thoughtfully among the headstones in the church cemetery, where tall stalks of sunlit grass surround some of the young who died for lack of grain a hundred years before. The headstones bear such familiar names as Larssen and Persson, the English equivalent of Smith and Jones; Bygren probably played with some of their relatives as a boy. Bluebells and daisies flower naturally between the stones, and some graves are adorned with gaudier store-bought flowers.
“We have an expression,” he says with a laugh. “Dig where you stand!”
After a moment, Bygren adds, “We are really data rich.” Data rich even when crop poor. “Everything happening in the family was recorded.”
Ever since the sixteenth century, the clergy has kept a fastidious ledger of births and deaths (with causes), as well as land ownership, crop prices, and harvests. Thanks to the clergy’s meticulous record-keeping, Bygren was able to gauge how much food was on hand when parents and grandparents were children. Överkalix provided a natural experiment where he could follow isolated families as they tumbled forward in time.
Common sense hints that if you’re creased by trauma, are a junk food junkie, or spend your days staring at lit screens while spring offers the likes of pink-petaled magnolias ruffling their flamingo feathers in the breeze, it may make you miserable and unhealthy, but it won’t affect the DNA of your unborn children. They may inherit your curly hair, gray eyes, musical ear reliable as a tuning fork, thin porcelain skin, or risk of a genetic disease such as Huntington’s, but they won’t suffer from your accidents and misdeeds. Their DNA won’t be damaged by your rotten choices in lifestyle, nor can you pass on all the wonderful feats you’ve accomplished, the wonders your senses have soaked in, the perils you’ve avoided. In that sense, they’re born with a clean slate and will become entangled in their own dramas and make their own questionable choices. Certainly they won’t be obese, get diabetes, or die young just because a grandparent binged during one tantalizingly rich harvest season after a year of brutal gourd-bellied hunger. Evolution doesn’t work that way or that fast—end of story. Or is it?
What Bygren found was quite different. He and the geneticist Marcus Pembrey, of University College London, began collaborating on groundbreaking studies that raised eyebrows and led to such headlines as “You Can Traumatize Your DNA,” “You Are What Your Grandparents Ate,” “Nurture Matters,” and “The Sins of Our Fathers” (in Exodus, God speaks of “visiting the iniquity of the fathers on the children and the children’s children”).
The ultimate immigrants, babies arrive in this world from a far country with no dry land, lugging helical clouds of ancient DNA, primed for survival, but seemingly ill equipped to face sudden changes in the environment. Yet it is possible to warn children and grandchildren about recent dangers. Episodes of near-starvation—or other extreme changes in the environment—tag the DNA in children’s nascent eggs and sperm. Then years later, when they have children of their own, new traits emerge, not because the traits serve the species well, but because of the parents’ specific stresses long before their children were conceived.
When Bygren looked at the children of Överkalix, he was surprised to discover that boys between the ages of nine and twelve who gorged during a bountiful season, inviting diabetes and heart problems, produced sons and grandsons with shorter life spans. And not by a negligible amount. Both sons and grandsons lived an average of thirty-two years less! In contrast, the boys who suffered a hunger winter, if they survived and grew up to have sons of their own, raised boys with health benefits—four times less diabetes and heart disease than their peers and life spans that averaged thirty-two years longer. Later studies found similar results among the girls, though at a younger age, since girls are born with a bevy of eggs and boys develop sperm in the prelude to puberty. During these growth windows, ripening eggs and sperm seem to be especially vulnerable to intel about the environment. Like a computer’s binary code, the marks tell switches to turn on or off in the cells. Then eggs and/or sperm ferry the message to the next generation, where they may indeed be lifesaving. On the other hand, they could usher in the onset of disease by equipping someone for a world that no longer exists. Problems detonate when one is biologically prepared for a radically different environment.
“The results are there,” Bygren says, solid as the iron ore enriching the folds of Norrbotten. “The mechanisms are not so clear.”
Shocking though the idea was, the evidence plainly showed that it only took a single generation to make indelible changes. That year of gluttony as a child set in motion a biological avalanche in the cells, dooming the children’s as yet unimagined grandchildren to a host of illnesses and vastly shorter lives than their peers. It’s as if they had inherited a genetic scar.
How and why this evolutionary sidestep happens is the focus of epigenetics, a new science that puts all the old-fashioned college debates about nature or nurture on the Anthropocene scrap heap of outmoded ideas. It also lays a heavier burden on the shoulders of would-be parents. Apparently, it’s never too soon to begin worrying about the health of your grandchildren.
The implications are staggering. Up until now, inheritance was a tale told by DNA; it lay exclusively in the genes. In the watch-how-you-step, deep-nurture world of epigenetics, proteins tag DNA by coiling around it, pythonlike, squeezing some genes tighter and loosening others, in the process switching them on or off, or leaving them on but turning the volume up or dialing it down to a whisper.
Changes in our genome took millions of years, but the epigenome can be changed quickly, for example, by simply adding a tiny methyl group (three hydrogen atoms glued to one carbon atom) or an acetyl group (two carbons, three hydrogens, and an oxygen). This “methylation” turns a gene off, and “acetylation” turns a gene on. Environmental stresses flip the switch, which makes sense, since in theory it prepares offspring for the environment they’re going to find. Diet, stress, prenatal nutrition, and neglect create especially strong marks, whose influence can be either good or bad. How the marks fiddle with your genes may be deadly in the long run, or may prolong your life. Exercise and good nutrition leave beneficial tags, smoking and high stress pernicious ones.
What changes isn’t the tool but how it’s used. It’s like the difference between wielding a hammer to tap in a picture nail or to smash a hole in a wall. Nature is thrifty, recycling the basics. It’s as if DNA were a tonal language using the same consonants and vowels, but speaking them with different inflections. In Mandarin Chinese, the world’s most widely spoken tonal language, how you voice the word “man” determines whether you mean “slow” or “deceive.” Exactly the same DNA funds heart, pancreas, and brain cells, yet they finesse different tasks. As genes are switched on and off, made to shout or whisper, their meaning and purpose shift. That’s why it’s merely an embarrassment that we have fewer genes than plants and nearly the same genes as chimpanzees. Gifted with the same libretto of genes, life forms intone them differently, and our own cells morph into skin, bone, lips, liver, blood. Epigenetics is providing clues to how this tonal magic is performed.
Pembrey’s fascinating hypothesis is that the Industrial Age ushered in a flood of rapid-fire environmental and social changes, and while genetic evolution struggled to keep up with them, it couldn’t adapt that fast. The speed of change was unprecedented, and our genes don’t evolve in just a few generations. But certain “epigenetic tags” clinging to those genes could. So the pesticides or hydrocarbons your great-grandmother was exposed to when she was pregnant may heighten the risk of ovarian disease in you, and you in turn might pass that risk on to your grandchildren. Ovarian cancer has been increasing to affect more than 10 percent of women over the past few decades, and environmental epigenetics offers a plausible reason why.
We only exist in relation to others and the world. This dialogue, a three-ri
ng circus among the genes, a perpetual biological tango performed by multitudes, deserves a better name than the unwieldy crunch of “epigenetics,” but the word is springing from many more lips as doctors search for clues in both a patient’s environmental exposure history and that of his parents.
“We’re in the midst of probably the biggest revolution in biology,” says Mark Mehler, chair of the Department of Neurology at Albert Einstein College of Medicine. “It’s forever going to transform the way we understand genetics, environment, the way the two interact, what causes disease. It’s another level of biology, which for the first time really is up to the task of explaining the biological complexity of life.”
“The Human Genome Project was supposed to usher in a new era of personalized medicine,” Mehler told the American Academy of Neurology at its annual meeting in 2011. “Instead, it alerted us to the presence of a second, more sophisticated genome that needed to be studied.”
Despite the DNA of twins, for example, they’re never perfect matches. If one has schizophrenia, the odds of her twin developing it are only 50 percent, not 100 percent as one might assume since they have identical genes. Twins have become an important part of epigenetic studies. So have children of Holocaust survivors, Romanian orphans who weren’t held and comforted enough, and children with stress-rattled or neglectful caregivers. From psychiatric epigenetics we’re learning how important a mother’s mood is to the fate of her fetus. The chemicals that swaddle and seep through a fetus can influence its future health, mood, and life span.
In 2004, Michael Meaney, whose lab at McGill University was studying maternal behavior, published his findings in Nature Neuroscience. Good mother rats, who licked their fourteen to twenty pups often and with care during the first week of life, produced nice calm pups. Standoffish mother rats who didn’t lick their pups much or neglected them entirely produced noticeably anxious pups. And as adults, the next generation of female rats mirrored their mothers’ behavior.
“For us, the Holy Grail was to identify the path that was being altered by this licking behavior,” Meaney says. “We identified one small region on the gene that responds to maternal care and directs changes in the brain cells.”
Meaney’s work is now looking at human child development. A highly stressed pregnant mother floods her fetus with glucocorticoids, which can reduce birth weight, shrink the size of the hippocampus (memory’s estate), and cripple the ability to deal with stress. Yet, as Meaney is the first to point out, many underweight babies turn out fine, which suggests that postnatal care must be able to reverse the ill effects. Environment and nurture do matter, and it doesn’t take long for their influence to show. In colonies of the desert locust, individuals are naturally shy and nocturnal. But if the population swells and overcrowding occurs, the densely packed grasshoppers give birth to gregarious, diurnal young. Or, in bird studies, if the mother lives in “socially demanding conditions,” holding high social rank, for example, her androgen level climbs. That leads to increased androgen in her eggs and produces more competitive chicks.
Is our moviegoer among the poor? As the health consequences of poverty drift into social medicine’s sights, ongoing human and animal studies link either enriched environments or impoverished ones to the health of children and grandchildren. Studies of the Dutch Hunger Winter in 1944–45 reveal that prenatal hunger can lead to schizophrenia and depression. In a U.K. study, poor prenatal nutrition is tied to a trio of risks for heart disease in older adults.
In other research, mothers who lived through the stresses of hurricanes and tropical storms while they were pregnant were more likely to have autistic children. Even if as an adult the redhead makes all the healthy choices, is happy during her own pregnancy, and becomes a doting mom, her child can still suffer from the stresses its neglected grandmother endured during the Great Depression. Or its grandfather suffered in Vietnam as a young recruit before she was even conceived. What her grandparents ate for breakfast matters.
Did our redhead’s father take Viagra? Thanks to such drugs, much-older men are siring offspring. What effect could so many older fathers, and aging genes, have on us and future generations? One unexpected finding is that, for some reason, older fathers endow their offspring with longer telomeres (which cap the ends of chromosomes like the tabs at the end of shoelaces do to keep them from fraying), a part of the gene that controls life span. So the children may live longer. On the other hand, older fathers are blamed for passing on mutations that can lead to such dreaded disorders as autism or schizophrenia. Dad’s diet was also important; if he was gluttonous, she may be more likely to develop diabetes. Fortunately, our moviegoer inherited telomeres long as a summer night.
None of this happens by unzipping and altering the codebook of DNA, yet it’s inherited by offspring. Epigenetics is the second pair of pants in the genetic suit, another weave of heredity, and although revising someone’s genome is hard, it’s relatively easy to change an epigenome. The marks are profound but not permanent. As a result, the field holds limitless promise.
“Genes can’t function independently of their environment,” Meaney says. “So every aspect of our lives is a constant function of the dialogue between environmental signals and the genome. The bottom line seems to be that parental care can have an even bigger impact than we ever dreamed on our children’s lives. We’re just starting to learn what that means.”
Yes, a trauma in your mother’s childhood could affect your health, and the health of your child—but it’s also reversible, even as an adult. In the McGill study, researchers were able to undo the chilly behavior of the second generation of mother rats by using epigenetic drugs to turn genes on or off.
The great promise of epigenetics is the possibility of curing cancer, bipolar disorder, schizophrenia, Alzheimer’s, diabetes, and autism by simply flipping the switches that tell some genes to wake up or work overtime, and others to lighten up or nap. Can we really hypnotize our genes like that, canceling out bad behavior and sparing innocent offspring before we plan to have any? The consensus is yes. Scientists have begun developing drugs such as azacitidine (given to patients with certain blood disorders) capable of silencing bum genes and spurring on healing ones. Many illnesses, such as ALS and autism, appear to be epigenetic, which puts them within reach. Three different types of epigenetic drug therapy are being actively investigated for schizophrenia, bipolar disorder, and other major psychoses. The FDA has already approved several epigenetic drugs, and in 2008 the National Institutes of Health (NIH) declared epigenetics “central” to biology and committed $190 million to understanding “how and when epigenetic processes control genes.” The Human Genome Project, completed in 2003, rightly celebrated as a wonder of human ingenuity, had only twenty-five thousand genes to map. The epigenome is much more complicated, with millions of telltale marks. So a full epigenome will take a while, but an international Human Epigenome Project is under way.
The good news is that these are problems with possible, if not simple, solutions: ban more environmental toxins known to trigger epigenetic havoc; work harder to ease famine, reduce poverty, and repair the ravages of war; and help people understand the long-term impact of their actions and the vital role that nurture plays in their families, societies, and environment. Genes may remember how they once behaved in parent and grandparent cells, but, fortunately, they can also learn healthy behaviors, based on use, just as muscles do. What you experience in your lifetime will become a vital part of your child’s legacy. Your adult experiences can rewire your genes in positive ways, and just as startlingly, the nurturing you do for friends, sweethearts, and other people’s children can have lasting epigenetic effects. Once that idea registers, it changes the relationship between generations, which suddenly have everything in common, and the tapestry of the human condition grows a little more visible, thread by thread. At the level of DNA’s phantom doormen, we can be connected to anyone and everyone.
There’s also a moral, social, and political lesson
: while humanitarian programs may seem nonessential, an extravagance of resources and spirit we can’t afford, epigenetics teaches us that, on the contrary, poor education, violence, hunger, and poverty leave scars on one generation after another in a way that ultimately affects the future health and well-being of whole societies. What happens to war-torn soldiers and civilians during and after battle leaves epigenetic traces to wound future generations, adding to a country’s problems, even in peacetime. The same is true of natural disasters, and we’ve seen plenty of both of late. Who knows what epigenetic aftermath will result? Genetic engineering may seem like a diabolical threat to us as a species, and we do need scrupulous oversight and control of such life forms. But the political and environmental choices we make—those with epigenetic repercussions—are equally powerful engines of change, ones we can often identify and fine-tune.
MEET MY MAKER,
THE MAD MOLECULE
Returning to our mystery redhead in the movie theater—what else could we learn about her from a strand of hair or blood sample? Her DNA profile, resembling a supermarket barcode, is a monumental accomplishment, but it’s only a fraction of her story. For a fuller picture of her health and heredity, we would need to include the teeming seashores of her microbes, the rest of her being—in fact, more than her being. Another self, a shadow self. At any moment, she is inseparable from trillions of her single-celled, single-minded, naked companions, some of whom don’t have her best interests at heart.
When she weighed herself earlier today, she may have deducted a pound or two for clothes and shoes. But did she take into account the roughly three pounds of microorganisms that inhabit her crevices and innards? Probably not. She’d need an atomic scale to start with, and anyway microbes are shifty, jumping off her peninsulalike feet and climbing aboard elbows pell-mell; they’re not easy to tally.