Don’t blame grandma yet, but your asthma may be her fault
Editor’s note: This story is part of a joint series by the PBS NewsHour and The Detroit News examining the latest research on the role chronic stress may play in the growing childhood asthma epidemic. Read more on The Detroit News’s website, and watch the full segment on Wednesday’s PBS NewsHour.
It’s natural to wonder if your environment is changing you. It’s no secret that smoking and pesticides are bad for your lungs and that exercise is good for your heart. But these things may actually change the function of our genes in ways that can be passed on to our children and grandchildren.
Enter epigenetics, a bridge for this burning question of nature versus nurture.
While genetics typically refers to the physical structure of DNA, epigenetics is a process. Epigenetics describes how environmental factors like stress, environmental toxins and nutrition can alter our DNA, the production of proteins and ultimately how a cell behaves. Unlike a genetic mutation, which adds or deletes DNA building blocks, an epigenetic change ornaments the building blocks of DNA. And those ornaments may have profound consequences on a life’s trajectory, especially if they happen early in development. But unlike a genetic mutation, which is permanent, an epigenetic shift is reversible.
As a field, the research is young, but early results suggest that epigenetics may chart the outcomes of autism, obesity, cancer and psychiatric disorders.
“At the end of the day, genetics and DNA hold your potential,’ said pediatric geneticist Lisa Joss-Moore of the University of Utah. “DNA is static, and it gives you what you can do. Epigenetics determines what you’re going to do with that potential.”
Plus, research argues that epigenetic changes can cross generations, meaning an organism’s environment might leave a lasting legacy. Emerging technologies could allow doctors to one day tweak an epigenetic malfunction and reverse a disease. Such tweaks are already happening with certain types of cancer. However, epigenetics runs the risk of being overblown, like stem cells or gene editing, before its full potential is validated.
The basics of epigenetics
DNA is shaped like a helix, and our bodies contain a lot of it. If placed in a single line, DNA in your body would stretch hundreds of times between the Earth and the sun. To fit inside a cell, DNA is spooled like yarn around blocks of proteins, called histones. These histones keep DNA packed tight and serve as brakes that regulate when and how often DNA genes get translated into proteins, allowing our cells and bodies to function normally. The first step of that process involves unraveling the DNA off the histones. To do so, histones are equipped with chemical tags that serve as switches. Two examples are acetylation and methylation. Chemically adding acetyl tags — acetylation — tends to unwind DNA and activate genes, whereas adding methyl tags — methylation — can activate or repress a gene.
These tags forms your epigenetic code, which influences your ability to be different.
“If you’ve got a crappy genome, you’re stuck with it. But if your epigenome is manipulated by the environment, then it can be manipulated both for good and for bad. That gives people back little more power to have some say in their outcome,” Joss-Moore said.
For instance, if your genome gave you brown hair, then epigenetics may dictate when it turns grey.
These epigenetic modifications respond to the environment, fine tuning how our DNA and cells behave when exposed to radiation, after eating a cheeseburger or when just sitting on the couch at home.
A time machine for cancer
Epigenetics is a potent weapon on the cancer battlefield. Cancer was formerly thought of as a disease of mutation or physical changes to DNA. Additions and deletions. These tweaks can swith on a gene called an oncogene, pushing a normal cell toward becoming cancerous. Mutations can also impair tumor suppressor genes, which keep normal cells from becoming malignant. A tumor arises through a collection of these mutations, though they differ for every type of cancer. No two cancer cells in a fully formed tumor are genetically identical.
Epigenetics adds extra layers of complexity, turning this one-dimensional puzzle into a Jenga board.
“The evidence for epigenetics being involved in cancer is very widespread. If you look at solid tumors and leukemias, there are tumor suppressor genes that we know are inactivated by epigenetic mechanisms in almost all of these tumors,” said Adam Karpf, a cancer biologist and epigeneticist at the University of Nebraska Medical Center.
It’s believed that exposure to environmental toxins like arsenic or some pharmaceuticals can push a cell toward becoming cancerous through epigenetics, though most of this evidence has been observed outside humans. Cancer biologists are taking advantage of these epigenetic mechanisms to change the fate of tumors.
“The evidence is very extensive at this point for epigenetics to be involved in virtually all human cancers,”Karpf said.
This manipulation is clearest with leukemias and other blood cancers. Epigenetic patterns are easily altered by the environment. But these changes are difficult to study. That’s because once you remove a cell from the body, its epigenome begins to change almost immediately. One of the best bodily tissues for epigenetic study is blood because it’s easy to remove and quickly prep for analysis.
Specifically, in some forms of leukemia, the enzymes responsible for DNA methylation are mutated, Karpf said.
Karpf said there are multiple anticancer drugs for inhibiting epigenetic processes approved by the Food and Drug Administration. The first entered the market 10 years ago. They are mainly used to treat blood cancers like acute myeloid leukemia and and myelodysplastic syndrome. Studies suggest that some of these drugs may help cancer cells revert back to their normal state.
“The hypothesis is these AML and MDS drugs are restoring normal phenotypes in the cancer-initiating cell population by reversing DNA methylation patterns,” Karpf said. “It’s very difficult to prove that mechanism in humans, but animal model experiments and clinical responses in humans suggest that’s probably what’s going on.”
Karpf says that there is a major push by pharmaceutical companies to develop new drugs for epigenetic targets, especially for solid tumors found in organs. His lab, for instance, is developing therapeutic approaches that make ovarian tumors more prone to being recognized by the immune system.
Folate may protect against autism but no one knows how much you should take
Anything you consume can modify the epigenome of a cell. Beer and cocaine consumption during pregnancy in rodents can alter the epigenome of pups, predisposing them for addiction. The antioxidant powers of vitamin-C can reprogram skin cells into stem cells in the lab, thanks to epigenetics, though it isn’t clear what that means for humans. And then there’s the case for folate, epigenetics and the prevention of autism.
“We know that there’s a link between maternal folate consumption during pregnancy and brain development in the fetus,” said Joss-Moore. Mothers are recommended to consume extra folate because the nutrient serves as a building block for DNA. This DNA synthesis is crucial for rapidly replicating cells, which feature prominently in growing fetuses and infants. Without enough folate, a child’s odds rise for developmental disorders like congenital heart disease and neural tube defects that cause mental retardation. The rate of neural tube defects has dropped by 25 to 30 percent since the Food and Drug Administration mandated folate fortification in food in 1998, and some argue additional folate could reduce the problem even further.
DNA synthesis is pegged as the major benefit of folate, also known as folic acid, but the compound can also spur epigenetic modifications, namely methylation.
“There are some nice studies with older people that have had a couple of years of folate supplementation with B12 vitamins. If you then look across the whole epigenome, there are some genes that have more DNA methylation following the folate supplementation,” Joss-Moore said.
Rodent studies have shown that folate can methylate autism-susceptibility genes, but it’s unclear if that relationship carries into humans, or if the result has a positive or negative effect. While a handful of human studies have observed a relationship where folate increases autism risk, the majority — 80 percent — argue that it decreases the chances of developing autism.
So how much should you take? At the moment, no one knows. For instance, in the geriatric study in which patients took B12 for two years, the scientists expected that the genome in blood cells would be massively methylated at the end, Joss-Moore said. It wasn’t, suggesting there’s an upper limit to folate’s influence on epigenetics.
Another problem is access to the organ of interest.
“We do know with epigenetics in general that it’s specific to the organ of interest. If I’m just looking at your blood profile, then I’m not getting a picture of how the DNA methylation is altered in your liver, your fat tissue, which is a big deal today in obesity research, or your brain in the case of autism,” Joss-Moore said.
Yet people aren’t comfortable with the idea of hacking away pieces of their body for research, and it’s doubtful if they ever will be. So for now, epigeneticists are waiting for a noninvasive technique to shine a light on our hard-to-reach organs, so scientists can further study which aspects of diet are crucial. At the moment, we don’t know, but the social value could be grand.
“If we can really understand how to optimize prenatal health from an epigenetic standpoint, then we have the ability to potentially deal not only with neonatal disease, but also long-term disease,” Joss-Moore said.
If you live in Michigan, your baby may be leading the epigenetics revolution
Building the connections between epigenetics and disease will take time. Epigenetics have been implicated in diseases like autism, schizophrenia, cancer and bipolar disorders — diseases that take years, if not decades, to develop. Plus, it’s suspected that epigenetics modifications early in life or before being born might be important, so getting an accurate picture may involve studies that last multiple lifetimes.
Toxicologist Dana Dolinoy, for instance, suspects that environmental exposures during infancy may trigger obesity later in life, and thanks to the state of Michigan, she may one day find an answer. The Michigan BioTrust for Health has conducted newborn screening for almost every child in the state since 1984. At birth, six drops of blood are collected from a baby’s heel, stored on paper cards and used to immediately screen for disorders like cystic fibrosis.
However, the blood spot cards have been a valuable tool for long-term research too. Michigan parents give consent at a child’s birth for anonymous research on the blood spots, but they can opt-out at any time. So if a scientist wants to conduct a geographical analysis — Did lead exposure in this town influence epigenetics markers versus this other town? — they can do so without needing to know the individuals and without getting consent.
“I’m involved with a study here in Michigan where we’re recruiting families and looking at lots of different risk factors for childhood obesity: sedentary lifestyle, video games, advertising. One of the things that we’ll ask is, ‘Could epigenetics at birth predict who will be obese later in life?” said Dolinoy, who works at the University of Michigan. That type of study requires knowledge of individual identities, and Dolinoy and her colleagues must personally request this information, but again, a parent can say no.
Consent is a sticky issue with DNA banking. Earlier this year, the U.S. National Institutes of Health published one of the largest collections of epigenome data ever amassed, which could only be accomplished through patient consent. All 50 states conduct newborn screening, yet a 2011 review found the rules on retaining those samples and confidentiality vary from state to state:
Information related to newborn screening is considered confidential in 26 states, but the limitations on that confidentiality vary. For example, in 1 state, information specific to individual newborns is considered confidential, but the information may be used for scientific research so long as the infant’s name is kept confidential. There is no requirement that other identifying information be omitted.
In four states — Utah, Washington, California and Maine — newborn blood samples become property of the government, though parents can file for ownership in the latter two. Seven states can give permission for research without parental consent. Texas was formerly part of this pack, but a 2009 lawsuit over the long-term storage of blood samples for research forced the state to change their policy. The resulting settlement also led to the destruction of approximately five million samples that had been collected without parental consent. (To learn about your state’s policy, go here.)
But Dolinoy points to multiple examples in which newborn screening provided important information on epigenetics and public health. Smoking during pregnancy is one example. Another is the “provocative” idea that a person’s lifestyle and exposure to toxins could influence their grandchild’s epigenetics. (Again, most of this research has been conducted in rodents, not people.)
Dolinoy says that scientists are still several years away from applying epigenetics to human health in terms of interventions and treatments, but there’s a “grand hope” in the field.
Maternal trauma may instill asthma susceptibility in a child due to epigenetics
Watch the full segment on the role of chronic stress in the childhood asthma epidemic on Wednesday’s PBS NewsHour.
Given that epigenetic modifications may cross generations in humans, the field lends itself to the biblical notion of “the sins of the father/mother.” Trauma is one arena where this concept may come to bear.
Rosalind Wright, a pediatrician at the Icahn School of Medicine at Mount Sinai in New York City, is studying how stress and poverty might leave a lasting impression for generations.
“There are some people who live in situations where they can’t get rid of the stressors, whether it’s financial challenges, whether you live in an unsafe neighborhood, so you are always on edge and afraid that something can happen,” Wright said. “Or perhaps a violent event has happened, and that trauma sticks and goes on and on for a person.”
This persistent stress can trigger illness, because our bodies can’t sustain a state of constantly being on edge. Our nervous system, immune system, stress hormones and organs try compensate, but eventually a person erodes, Wright said, and one manifestation of this process is asthma.
“An air pollutant or an allergen that’s breathed in through the nose and gets into the lungs triggers airway narrowing that manifests as asthma stress. A psychological and emotional experience sets off those same kinds of responses,” Wright said. “Our studies show that stress has an equal-in-magnitude effect on asthma, whether you are talking onset or triggering asthma attacks on par with tobacco smoke.”
And her team and others are examining whether experiences in the womb or before conception can pass this stress-induced disposition for asthma onto their offspring. Multiple rodent studies have shown the trauma of inattentive parenting can instill a generational legacy of poor parenting that’s associated with a change in epigenetics. Exposure to tobacco smoke during pregnancy or early childhood can increase the risk of asthma, so perhaps chronic stress does the same?
Epigenetics may factor into the equation, Wright said, but those investigations are ongoing.
Epigenetics may ripen the tomatoes
Epigenetics extends outside the realm of humans. For instance, eating royal jelly separates queen bees from worker bees through epigenetics.
Another arena is crops. Emerging research shows that environmental conditions like drought shift the epigenome of plants and potentially alter their outcomes. An epigenetic mutation can stop a tomato from ripening or switch the sex of a melon.
“These modifications are certainly involved in how plants respond to drought or extreme — high and low — temperatures,” said University of Minnesota plant biologist Nathan Springer. “It is less clear whether these changes are actually heritable and would affect the offspring.”
However, scientists have started screening plants for epigenetic shifts to get clues about plant breeding. The best example in recent history, Springer says, is the “Karma” story with palm oil. Oil palms are grown on large farms in the tropics, but most trees have been produced using lab procedures to culture genetically uniform crops. One consequence of this is that a sizable percentage of plants exhibit something called “mantling.” Mantling is a trait seen in cloned plants in the lab, when they stop yielding a crop.
“This trait is not visible for many years (until the plants reach maturity), however, the plants that are mantled do not produce any usable crop,” Springer said.
In a study published earlier this year, a group of researchers profiled the epigenetics of oil palm plants to examine how lab cloning might cause mantling. They found an epigenetic marker that could predict which plants would mantle. Farmers could use this knowledge to cull the poor performers, Springer said. He continued that investigating such epigenetic traits may also reveal which plants are most susceptible to climate change.
The dangers of epigenetics hype and disenfranchisement
Like any emerging field of health, epigenetics falls victim to hype. So far, no studies have shown that humans can pass an epigenetic trait onto their children that goes on to cause a disease. Yet media stories and health blogs have already argued that lifestyle choices can control the destiny of your kids.
“We don’t have enough knowledge about human genetics to be writing prescriptions about behavior changes during pregnancy or childhood, like the ones already seen in the media,” said Eric Juengst, a bioethicist at the University of North Carolina, Chapel Hill.
He continued that unfounded hype about science tends to backfire by undermining public trust. If a genomics researcher promises a cure and doesn’t deliver, then patients begin to question why they forked over their DNA in the first place.
With epigenetics, a socioeconomic issue of class disparities may surface too.
“One example of parents who are the most vulnerable to epigenetic risk might be those exposed to toxins like pesticides. Well, who are the parents? They’re often disenfranchised migrant workers in California or elsewhere,” Juengst said. “To give the advice that to be good parents, they need to avoid exposure to pesticides is putting them in a pretty impossible situation, since farming is their livelihood. Also, it takes the focus off the upstream, wherein the same research suggests that maybe farm owners should reduce pesticide exposure in general.”
He puts the responsibility on everyone disseminating messages about epigenetics — from researchers to journalists. The principle responsibility, he says, is on the scientific community to frame its messages as modestly as possible. Media reps, science journalists and public health mediators must accurately package the findings, and finally, clinicians who are trying to help parents and prospective parents must be sages in terms of their warnings.
“Take warnings about intergenerational epigenetics in humans with a grain of salt,” Juengst said. “Look forward to more research, but don’t jump to immediately feeling responsible for your grandchildren’s genetics, to the extent that some messages might urge us to.”