Inheritance: How Our Genes Change Our Lives--and Our Lives Change Our Genes

by Moalem MD PhD, Sharon

  Now, we might not look like bees. And we might not feel like bees. But we share a striking number of genetic similarities with bees, including Dnmt3.5

  And just like those bees, our lives can be momentously impacted by genetic expression, for better or for worse.

  Take spinach, for instance. Its leaves are rich in a chemical compound called betaine. In nature or on a farm, betaine helps plants deal with environmental stress, such as low water, high salinity, or extreme temperatures. In your body, though, betaine can behave as a methyl donor—part of a chain of chemical events that leaves a mark on your genetic code. And researchers at Oregon State University have found that, in many people who eat spinach, the epigenetic changes can help influence how their cells fight back against genetic mutations caused by a carcinogen in cooked meat. In fact, in tests involving laboratory animals, researchers were able to cut the incidence of colon tumors nearly in half.6

  In a very small but important way, compounds within spinach can instruct the cells within our bodies to behave differently—just like royal jelly instructs bees to develop in different ways. So yes, eating spinach seems to be able to change the expression of your genes themselves.

  Remember when I told you that Mendel, if Bishop Schaffgotsch had not curtailed his work with mice, might have stumbled upon something even more revolutionary than his theory of inheritance? Well, now I’d like to tell you about how that idea finally came to light.

  First of all, it took time. More than 90 years had passed since Mendel’s death when, in 1975, geneticists Arthur Riggs and Robin Holliday, working separately in the United States and Great Britain, respectively, almost simultaneously came upon the idea that, while genes were indeed fixed, they could perhaps be expressed differently in response to an array of stimuli, thus producing a range of traits rather than the fixed characteristics commonly thought to be associated with genetic inheritance.

  Suddenly, the idea that the way genes are inherited could only be changed by the epically slow process of mutation was thrown into immediate dispute. But just as Mendel’s ideas had been roundly ignored, so too were the theories being offered by Riggs and Holliday. Once again, an idea about genetics that was ahead of its time failed to gain traction.

  It would be another quarter century before these ideas—and their profound implications—would gain broader acceptance. And that came as the result of the striking work of a cherub-faced scientist named Randy Jirtle. Like Mendel, Jirtle suspected that there was more to inheritance than met the eye. And, like Mendel, Jirtle suspected the answers could be found in mice.

  Experimenting with agouti mice, which carry a gene that renders them plump and bright orange like a Muppet, Jirtle and his associates at Duke University came upon a discovery that, at the time, was simply stunning. By doing nothing more than changing the diet of females by the addition of a few nutrients such as choline, vitamin B12, and folic acid, starting just before conception, their offspring would be smaller, mottled brown, and altogether more mouse-like in appearance. Researchers would later discover that these mice were less susceptible to cancer and diabetes as well.

  Same exact DNA. Completely different creature. And the difference was simply a matter of expression. In essence, a change in the mother’s diet tagged her offspring’s genetic code with a signal to turn off the agouti gene, and that turned-off gene then became inherited and was passed down across generations.

  But that’s just the beginning. In the fast-paced world of twenty-first-century genetics, Jirtle’s Muppets have already been relegated to syndicated reruns. Every day we’re learning new ways to alter genetic expression—in the genes of mice and men. The question isn’t whether we can intervene; that’s now a given. Now we’re examining how to do it with new drugs that are already approved for human use, in ways that will hopefully result in longer and healthier lives for ourselves and for our children. What Riggs and Holliday theorized about—and what Jirtle and his colleagues brought into popular acceptance—is now known as epigenetics. Broadly, epigenetics is the study of changes in gene expression that result from life conditions, such as those seen in honeybee larvae that are doused in royal jelly, without changes in the underlying DNA. One of the fastest growing and most exciting areas of epigenetic study is its heritability, the investigation of how these changes can impact the next generation, and every generation down the line.

  One common way changes in genetic expression occur is through an epigenetic process called methylation. There are many different ways in which DNA can be modified without the underlying string of nucleotide letters being altered. Methylation works by the use of a chemical compound, in the shape of three-leaf clovers made up of hydrogen and carbon, that is attached to DNA that alters the genetic structure in such a way as to program our cells to be what they’re supposed to be and to do what they’re supposed to do—or what they’ve been told to do by previous generations. Methylation “tags” that turn genes on and off can give us cancer, diabetes, and birth defects. But don’t despair—because they can also affect gene expression to give us better health and longevity.

  And such epigenetic changes seem to have consequences in some unexpected places. For instance, at a summer weight-loss camp.

  Genetic researchers decided to follow a group of 200 Spanish teens who were on a 10-week quest to battle the bulge. What geneticists discovered was that they could actually reverse engineer the campers’ summer experience and predict which of the teens would lose the most weight depending on the pattern of methylation—the way their genes were turned off or on—in around five sites in their genome before summer camp even began.7 Some kids were epigenetically primed to lose the bulge at summer camp while others were going to keep it on, despite diligent adherence to their counselors’ dietary protocol.

  We’re now learning how to apply the knowledge gained from studies such as these to capitalize on our own unique epigenetic makeup. What the teenagers’ methylation tags teach us is how critical it is to get to know our own distinctive epigenome in matters of weight loss, and so much else. Learning from these Spanish summer campers, we can start to mine our epigenome to find the information we need for the most optimal weight-loss strategies. For some of us that may mean saving on the exorbitant fees of a summer weight-loss adventure that is destined not to work.

  But far from being static, our epigenome, along with the DNA that we’ve inherited, can also be impacted by what we do to our genes. We’re quickly learning that epigenetic modifications, like methylation, are remarkably easy to impact. In recent years geneticists have devised a number of ways to study and even reprogram methylated genes—to turn them on and off, or to crank the volume up or down.

  Changing the volume of our genetic expression can mean the difference between a benign growth and a raging malignancy.

  These epigenetic changes can be caused by the pills we swallow, the cigarettes we smoke, the drinks we consume, the exercise classes we attend, and the X-rays we undergo.

  And we can also do it with stress.

  Building on Jirtle’s work on agouti mice, scientists in Zurich wanted to see whether early childhood trauma could impact gene expression, so they stole pup mice away from their mothers for three hours, then returned the blind, deaf, and furless little things to their mommies for the rest of the day. The next day, they did it again.

  Then, after 14 consecutive days, they stopped. Eventually, as all mice do, the little ones gained sight and hearing, grew some fur, and became adults. But having suffered two weeks of torment, they grew up to become significantly maladjusted little rodents. In particular, they seemed to have trouble evaluating potentially risky places. When put in adverse situations, instead of fighting or figuring it out, they just gave up. And here’s the amazing part: They transmitted these behaviors to their own pups—and then to the offspring of their offspring—even if they had no involvement whatsoever in the rearing.8

  In other words, a trauma in one generation was genetically present two generations dow
n the line. Incredible.

  It’s definitely worth noting here that the genome for a mouse is about 99 percent similar to ours. And the two genes impacted in the Zurich study—called Mecp2 and Crfr2—are found in mice and people alike.

  Of course, we can’t be sure that what happens in mice will happen in humans until we do, in fact, see it. That can be challenging to do, because our relatively long lives make it hard to conduct tests that explore generational changes, and when it comes to humans, it’s a lot harder to separate nature and nurture.

  But that doesn’t mean we haven’t seen epigenetic changes related to stress in humans. We most certainly have.

  Remember when I asked you to go back to the seventh grade? For some of us going back that far might evoke some rather unpleasant memories, events that, given a choice, we’d rather not recall. The real numbers are hard to come by, but it’s thought that at least three quarters of all children have been bullied at some point in their lives, which means there’s a good chance you were on the receiving end of such unfortunate experiences yourself while you were growing up. And as some of us have become parents since then, the concern for our children’s own experiences and safety both at school and beyond has only grown.

  Until very recently, we’ve been thinking and speaking about the serious and long-term ramifications of bullying in predominantly psychological terms. Everyone agrees that bullying can leave very significant mental scars. The immense psychic pain some children and teens experience can even lead them to consider and act on desires to physically harm themselves.

  But what if our experiences of being bullied did a lot more than just saddle us with some serious psychological baggage? Well, to answer that question, a group of researchers from the UK and Canada decided to study sets of monozygotic “identical” twins from the age of five. Besides having identical DNA, each twin pair in the study, up until that point, had never been bullied.

  You’ll be glad to know that these researchers were not allowed to traumatize their subjects, unlike how the Swiss mice were handled. Instead, they let other children do their scientific dirty work.

  After patiently waiting for a few years, the scientists revisited the twins where only one of the pair had been bullied. When they dropped back into their lives, they found the following: present now, at the age of 12, was a striking epigenetic difference that was not there when the children were five years old. The researchers found significant changes only in the twin who was bullied. This means, in no uncertain genetic terms, that bullying isn’t just risky in terms of self-harming tendencies for youth and adolescents; it actually changes how our genes work and how they shape our lives, and likely what we pass along to future generations.

  What does that change look like genetically? Well, on average, in the bullied twin a gene called SERT that codes for a protein that helps move the neurotransmitter serotonin into neurons had significantly more DNA methylation in its promoter region. This change is thought to dial down the amount of protein that can be made from the SERT gene—meaning the more it’s methylated the more it’s “turned off.”

  The reason these findings are significant is that these epigenetic changes are thought to be able to persist throughout our lives. This means that even if you can’t remember the details of being bullied, your genes certainly do.

  But that’s not all these researchers found. They also wanted to see if there were any psychological changes between the twins to go along with the genetic ones that they observed. To test that, they subjected the twins to certain types of situational testing, which included public speaking and mental arithmetic—experiences most of us find stressful and would rather avoid. They discovered that one of the twins, the one with a history of being bullied (with a corresponding epigenetic change), had a much lower cortisol response when exposed to those unpleasant situations. Bullying not only turned those children’s SERT gene to low, it also turned down their levels of cortisol when stressed.

  At first this may sound counterintuitive. Cortisol is known as the “stress” hormone and is normally elevated in people under stress. Why, then, would it be blunted in the twin who had a history of being bullied? Wouldn’t you think they would be more stressed in a heightened situation?

  This gets a little complicated, but hang tight: As a response to the persistent bullying trauma, the SERT gene of the bullied twin can alter the hypothalamic-pituitary-adrenal (HPA) axis, which normally helps us cope with the stresses and tumbles of daily living. And according to the scientists’ findings in the bullied twin, the greater the degree of methylation, the more the SERT gene is turned off. The more it’s turned off, the more blunted the cortisol response. To understand the sheer depth of this genetic reaction, this type of blunted cortisol response is also often found in people with post-traumatic stress disorder (PTSD).

  A spike of cortisol can help us through a tough situation. But having too much cortisol, for too long, can short-circuit our physiology pretty quickly. So, having a blunted cortisol response to stress was the twin’s epigenetic reaction to be being bullied day after day. In other words, the twin’s epigenome changed in response to protect them from too much sustained cortisol. This compromise is a beneficial epigenetic adaptation in these children that helps them survive persistent bullying. The implications of this are nothing short of staggering.

  Many of our genetic responses to our lives work in such a fashion, favoring the short over the long term. Sure, it’s easier in the short term to dull our response to persistent stress, but in the long run, epigenetic changes that cause long-term blunted cortisol responses can cause serious psychiatric conditions such as depression and alcoholism. And not to scare you too much, but those epigenetic changes are likely heritable from one generation to the next.

  If we’re finding such changes in individuals like the bullied twin, then what about traumatic events that affect large swaths of the population?

  It all started, tragically, on a crisp and clear Tuesday morning in New York City. More than 2,600 people died in and around New York’s World Trade Center on September 11, 2001. Many New Yorkers who were in direct proximity to the attacks were traumatized to the point of suffering from post-traumatic stress disorder in the months and years to come.

  And for Rachel Yehuda, a professor of psychiatry and neuroscience at the Traumatic Stress Studies Division at the Mount Sinai Medical Center in New York, the terrible tragedy presented a unique scientific opportunity.

  Yehuda had long known that people with PTSD often had lower levels of the stress hormone cortisol in their systems—she’d first seen that effect in combat veterans she studied in the late 1980s. So she knew where to start when she began looking at samples of saliva collected from women who were at or near the Twin Towers on 9/11, and who were pregnant at that time.

  Indeed, the women who ultimately developed PTSD had significantly lower levels of cortisol. And so did their babies after birth—especially the ones who were in the third trimester of development when the attacks occurred.

  Those babies are older now, and Yehuda and her colleagues are still investigating how they’ve been impacted by the attacks. And they’ve already established that the children of the traumatized mothers are likely to become distressed more easily than others.9

  What does all this mean? Taken together with the animal data we now have, it is safe to conclude that our genes do not forget our experiences, even long after we’ve sought therapy and feel that we’ve moved on. Our genes will still register and maintain that trauma.

  And so the compelling question remains: Do we or do we not pass on the trauma we experience, be it bullying or 9/11, to the next generation? We previously thought that almost all of these epigenetic marks or annotations that were made on our genetic code, like those made in the margins of a musical score, were wiped clean and removed before conception. As we prepare to leave Mendel behind, we are now learning that this is likely not the case.

  It is also becoming apparent that there are actual
ly windows of epigenetic susceptibility in embryonic development. Within these important time frames, environmental stressors such as poor nutrition affect whether certain genes become turned off and on and then affect our epigenome. That’s right, our genetic inheritance becomes imprinted during pivotal moments of our fetal lives.

  When exactly those moments occur no one yet knows precisely, so to be safe, moms now have a genetic motivation to watch their diets and stress levels consistently throughout gestation. Research is now even showing that factors such as a mother’s obesity during pregnancy can cause a metabolic reprogramming in the baby, which puts the baby at risk for conditions such as diabetes.10 This further buttresses the growing movement within obstetrics and maternal-fetal medicine that discourages pregnant woman from eating for two.

  And, as in the example of the traumatized Swiss mice, we’ve already seen that many of these epigenetic changes can be passed on from one generation to the next. Which makes me think that the likelihood is rather high that in the coming years we’ll have overwhelming evidence that humans are not immune from this type of epigenetic traumatic inheritance.

  In the meantime, given the tremendous amount we’ve learned about what inheritance really means and what we can do to impact our genetic legacy—in good ways (spinach, perhaps) and bad (stress, it would appear)—you are far from helpless. While it may not always be possible to break completely free from your genetic inheritance, the more you learn, the more you will come to understand that the choices you make can result in a big difference in this generation, the next one, and possibly everyone else down the line.

  Because what we do know is that we are the genetic culmination of our life experiences, as well as every event our parents and ancestors ever lived through and survived—from the most joyous to the most heartrending. By examining our capacity to change our genetic destiny through the choices we make and then pass those changes along through generations, we are now in the midst of fully challenging our cherished Mendelian beliefs regarding inheritance.