December 21, 2023 | There is mounting evidence that epigenetics—the molecular processes that influence how genes are expressed—is an equally if not more important driver of disease conditions and phenotypic differences than genetics. That means that accelerating the shift from reactionary medicine to preventive care is going to require biomarkers of these heritable and reversible changes, according to Michael Skinner, professor of biology at Washington State University.
Skinner and his colleagues have to date identified the epigenetic signatures of half a dozen diseases, he says. These include female rheumatoid arthritis, male infertility, preterm birth, and, as was most recently reported in Epigenetics (DOI: 10.1080/15592294.2023.2268834), obesity (others are in review or pending). Next up will be a biomarker signaling susceptibility to preeclampsia in pregnancy.
All diseases likely have phenotypic variations driven by epigenetics, says Skinner. This in no way contradicts Darwin’s population-based theory that the environment causes adaptations allowing only certain populations to survive. The characteristics generated and passed on via epigenetics are subject to the same mechanisms of evolution as changes in DNA sequence and can likewise influence survival.
For much of the past century the prevailing thought has been that genes are destiny and that the principle extended to obesity, which wasn’t even recognized as a disease until the late 1990s, Skinner says. But a succession of studies over the past 20 years has made clear that repeated environmental exposures have very little effect on the genetics of individuals.
In terms of an explanation for obesity, several massive genome-wide association studies have effectively proved that few clues can be found in the DNA sequence of affected individuals. Roughly one in 100 obese people have a genetic mutation that might explain their condition.
In similar studies that instead look at epigenetics, “generally 90% to 95% of people with the pathology have an epigenetic shift,” he says. Public perceptions about obesity nonetheless remain woefully misaligned with this biological reality.
It is highly infrequent that people are obese simply because they eat more than their thinner counterparts, he points out. Preclinical studies have shown that among mice put on the exact same diet and exercise regime only those susceptible to obesity gain excessive pounds, making this a “true molecular-based phenomenon.”
Much obesity research has been done attempting to get at reasons why some individuals are prone to wright gain while others are protected, including a longitudinal study of adult Finnish twins newly published in Obesity (DOI: 10.1002/oby.23906) that points to body mass index (BMI) trajectories. “Most studies do not deal with underlying molecular processes,” says Skinner.
In his view, “it is maybe not so much the individual that’s obese... [but] the general public.” Obesity is a disease pathology that has and will continue to become more pervasive, he says.
Skinner believes that susceptibility to obesity has risen over the past three to four generations because of exposure to environmental chemicals in the air we breathe and the soil in which our food is grown. Various chemicals that notoriously include DDT, the insecticide banned in the U.S. since 1972, have modified the germline of exposed individuals to make the current generation more obesity prone.
This idea is backed by a study where rats were exposed to DDT, Skinner says. “We took it out three generations and 50% of the population had obesity.”
This doesn’t mean diet and exercise aren’t critical, he adds. “The people who take that seriously can probably control their obesity a little bit more, but we can’t be pointing our fingers and saying this is just because of what you ate.”
The scary part is that the problem may well get worse before it gets better, says Skinner.
Glyphosate, the active ingredient in RoundUp, is one of the most heavily used herbicides in the world today. While it has dramatically increased food production as intended, it has also “recombinantly changed” soy, corn, and other agricultural staples and takes up to 15 years to decay in the soil after being sprayed in the field, he says. It is therefore difficult to buy glyphosate-free food products, including organic ones unless the farm doing the growing knows for certain what was put in the soil over the last decade and a half.
“We are being exposed just through our diet to something that we know has some fairly dramatic effects,” says Skinner. “It was designed to be a very safe compound... so our current generation is not affected, but our grandchildren will inherit this epigenetic shift and they will have a much higher degree of disease and pathology due to that.”
The Centers for Disease Control and Prevention indicates that overall obesity prevalence in the U.S. now sits at close to 50%, he reports, albeit with significant differences depending on where people live, their race/ethnicity, education, and age. Consequently, roughly half the population faces a shortened lifespan as well as greater susceptibility to a host of other diseases.
If chemical exposures continue to climb over the next 25 years, exacerbated by climate change, the obesity rate could well soar to between 75% and 80%, he says. That would make obesity the national norm.
The latest study by Skinner and his colleagues was conducted in 22 twin pairs who were genetically similar but discordant for obesity, which allowed the investigation to focus on the role of epigenetics. One sibling had a BMI of 30 or higher, meeting the standard definition for obesity, while the other sibling was in the normal range of 25 and below. In the cells from the twin siblings who were obese, researchers found similar epigenetic changes to DNA methylation regions controlling gene activity.
Since the epigenetic signature of obesity was found in cheek cells and not fat cells suggests that it is systemic and may have been triggered early in one twin’s life, Skinner says. More broadly, the systemic nature of epigenetic changes is evidenced by the fact that each of the 270 cell types in the body has a unique way of reading its genetic instructions, which is what drives cell specificity, he points out.
The changes would in fact explain why there are 270 cell types when the genetic sequence in every one of them is essentially the same. “Your body is essentially controlled by epigenetics rather than indirectly regulating... gene expression.”
Given that epigenetics determines cell function, epigenetic shifts in cells retrieved by a simple cheek swab test correlate with what’s happening in those cell types throughout the body, he explains. And some of those cells are going to be more susceptible to disease than others, providing an explanation of their molecular origin and where environmental exposures are having their effects.
In the future, Skinner and his team plan to expand their epigenome-wide association approach to a general population and numerous other disease conditions, including neurodegenerative and cardiovascular diseases, to identify new biomarkers so preventive steps can potentially be taken earlier in patients’ life, Skinner says. If such a biomarker were found for breast cancer, for example, women flagged for the condition in their 30s and 40s might be given chemotherapy prophylactically to delay or prevent its onset later in life, he offers as an example. “Today we don’t know who to give [a preventive therapeutic] to because we have no concept of who is going to be susceptible and who is not.”
Studies to date have been entirely preclinical and efforts are now underway to replicate the findings in larger populations, says Skinner. Translating epigenetic biomarkers from the lab to the clinic will require the resources of a commercial firm with regulatory know-how but could well be a reality within the next five to 10 years. Companies are already starting to look at several of the existing biomarkers, he reports.
If disease susceptibility can be detected early in life, then preventive steps could be taken to either delay or prevent its onset, says Skinner. In terms of obesity, the epigenetic signature might be turned into a screening test done in people in their teens of early 20s (i.e., old enough to provide medical consent) who, if found to be at risk, might then take countermeasures including lifestyle changes and, ultimately, preventive therapeutics.
Several anti-obesity drugs are already on the market to treat individuals who are obese and need help taking and keeping off the pounds. Obesity-prevention drugs are actively under investigation and doctors are going to need help knowing who to prescribe them to, which is where the epigenetic biomarker comes in, Skinner says.
In the field of metabolism, he notes, therapies are being developed that endeavor to alter the function of fat cells. But until preventive therapeutics are available in the clinic, the only option open to obese individuals is the personal choice to exercise substantially more and consume considerably less than people without the disease who don’t have to go to such lengths to maintain a healthy weight.
Had slender rather than obese individuals been enrolled in the latest epigenome-wide association study, Skinner says he expects it would have found an epigenetic signature describing their ability to keep off the extra pounds. It would perhaps hold some clues to choices and exposures favoring a highly effective metabolism.
Agricultural practices may eventually change to help reverse the seemingly inevitable course of obesity-favoring events, says Skinner. The U.S. is unlikely to ban the use of glyphosate, but the Europeans might and when they do farmers in the states may suddenly find themselves fighting for market share with glyphosate-free labeled products.