How Portlanders Are Forging the Frontier of Epigenetics
Two hundred years ago, the Swedish parish of Överkalix was a rough place to grow up. The little township experienced months of darkness, followed by months of endless sun. The rocky soil and permafrost barely kept a few hundred farmers alive. In 1812, widespread crop failure led to outright famine.
But then came 1813 and ’14, good years—very good years. A veritable Överkalix bonanza of potatoes, bread, butterfat, and red lingonberries poured forth, and mothers urged their boys to eat, eat, eat.
Decades later, a strange phenomenon manifested: the grandsons of men who had been well-fed 9- and 10-year-old boys during Överkalix’s feast years started dying young. Grandsons of men who had been the same age during the famine lived longer. Even taking into account wealth and social status, the outcome was a 32-year difference in life span for boys.
Even more strangely, the scientific saga that begins with those long-gone men of Överkalix leads to modern-day Portland, where about 60 researchers at Oregon Health & Science University are investigating a potentially radical new approach to ending chronic disease. Their discoveries could upend our understanding of how traits pass from one generation to the next.
“This work has invigorated the scientific community,” says Dr. Kent Thornburg, who leads this area of research and experimentation at OHSU. “We used to think genetics—the gene code—explained everything, in addition to a few behavioral choices people made.”
Everyone knows that eating spinach in your lifetime won’t give you Popeye-armed sons, just as breaking a leg on a black diamond run won’t result in broken-legged offspring. So why would a boy’s diet in one generation have an effect on the life span of his grandson? Inherited traits are based on genes, not behavior. Random mutation and variation. Survival of the fittest. Darwin! Right?
Turns out, Darwin may have missed a few things.
Thornburg and his colleagues work in a new field of inquiry called epigenetics—literally, “above the genes”—which seeks to understand how behaviors and experiences in one individual’s lifetime can create inheritable changes across multiple generations.
The epigenome tells genes to be active, or not. The metaphor of a light switch invariably comes up when scientists try to explain the concept. Stresses—nutritional, environmental, and perhaps even social—can cause those molecules to switch parts of the genome on or off. In other words, though the underlying gene doesn’t change, the way it actually expresses itself does.
Scientists around the world are trying to figure out how epigenetic changes in one generation affect future generations on a wide array of health issues, including heart disease, alcoholism, obesity, and depression. In Portland, Thornburg directs the Moore Institute for Nutrition and Wellness at OHSU, where investigators have landed about $14 million in grants since 2009 to probe this new avenue for understanding health. The OHSU center is complemented by a Portland State University study center working on the practical policy implications of the research.
Slight, white-haired, and soft-spoken, Thornburg has a warmly earnest mien. He describes epigenetics as the “fastest-moving field in all of medicine.” He says things that are known now—unknown only five or 10 years ago—have the potential to transform how we approach conditions such as diabetes, obesity, and heart disease. “This will drive public health policy in a way that we haven’t seen before,” he says.
The potential importance of epigenetics in the modern era—in Oregon alone, diabetes and obesity rates have doubled in the past decade—only make the field’s origin story more unlikely: it’s a tale of old data and odd connections, with characters separated by decades and continents.
A woman named Ethyl Burnside, England’s first Lady Inspector of Midwives, possessed a burning passion for writing things down. From 1911 to 1940, she logged 3,000 miles per year, cycling through the villages of Hertfordshire to give midwives scales, easy-read thermometers, notebooks, and exhortations to use them—which they did, despite protests from doctors who saw all this record-keeping as a waste of time.
Burnside died in 1953, but her records survived. In the 1980s, a British epidemiologist named Dr. David Barker dug out her notes on birth weight and infant health, and compared them with causes of illness and death for the individuals in the regions where she had worked. At the time, Barker (by all reports humorous and, at times, vexingly obstinate) was painstakingly plotting out mortality rates for the leading causes of death—influenza, heart disease, injury—in England and Wales.
The maps Barker and his team created pointed to a startling conclusion: some diseases seemed more closely linked to place than to lifestyle. In 1986, Barker published a paper in the Lancet, Britain’s premier medical journal, arguing that the birth weight of a particular individual (which he could access thanks to Burnside’s records) might be more important to his or her cardiovascular health than genetics or adult habits such as diet, exercise, or smoking. Birth weight, of course, can be the result of many things. But most often, low birth weight is a sign of poor nutrition or other stresses experienced in the womb. Its most significant determinants are the mother’s health, nutrition, and lifestyle. Some of these factors, of course, depend on her health and nutrition during pregnancy, but others go much further back—to a woman’s adolescence, and even to her mother’s adolescence.
In other words, the behavior and experiences—not just the genes—of one generation influence the health of their children...and their children’s children.
If this idea rings a distant bell from your high school science classes, the name you’re looking for is Lamarck: Jean-Baptiste Pierre Antoine de Monet, Chevalier de Lamarck, to be precise. A hungry giraffe best illustrated Lamarck’s theory of how species evolve. The giraffe stretched her neck out toward sweet acacia leaves, and as a result passed on a longer neck to her offspring. Feel free to chuckle; most scientists since 1820 have. Certainly, since Charles Darwin put forward his theories of natural selection and random mutation in the 1860s, Lamarck hasn’t gotten much love.
Barker quickly became a lightning rod, as rival scientists set out to prove his Lamarck-esque hypothesis wrong: What grandfathers eat shouldn’t determine their grandson’s age of death. Birth weight shouldn’t be more predictive of cause of death than lifestyle. In 1988, Thornburg met the embattled Barker at a conference in England. Barker asked Thornburg point blank what he thought about his big idea.
“I didn’t even know if I believed it,” Thornburg recalls. “Nobody believed it, until the biological data started coming in. But I liked David. We became friends immediately.”
In 2003, Barker retired from his post in England at the age of 65. At Thornburg’s invitation, he moved to Portland. The two doctors combined their areas of expertise—epidemiology and heart disease—to develop OHSU as the leading research institute on what is now called “developmental origins of health and disease,” or DOHaD.
In a 2007 New Yorker profile on his life and work, Barker is revealed as both a scientific revolutionary and a would-be social revolutionary. His research pointed to a flaw in how public policy looks at health (and particularly the health of poor people): as a barometer of good or bad personal choices. He agitated to change how doctors, nutritionists, and policy makers took on chronic disease. As he put it at the time: “There were some pretty good indications that the answer was not going to lie in the way that poor people lead their lives as adults.”
Thornburg speaks warmly of his friend and colleague, who died last August. The link that Barker discovered between the “first 1,000 days” after conception and permanent, inheritable changes in the body’s structure, physiology, and metabolism is now known as the Barker Theory—and is now widely accepted, even if the mechanisms are not yet fully understood. His efforts to understand and refine this theory were summarized in his 2008 book, Nutrition in the Womb.
In two moments in life, the body is especially sensitive to the kinds of stresses that result in lifelong and inheritable changes in how genes express themselves: the period just before adolescence, as with the boys from Overkalix, and the first 1,000 days—from conception through the first two years of a child’s life—as with the babies weighed by Ethyl Burnside.
“We know that stress changes the gene expression. We know that some of those changes are inheritable,” Thornburg says. “But we’re not sure how it works.”
And yet, very little research has been done on fetal and newborn babies and young children. Billions are spent to understand heart disease, but just about all of it goes to understanding risk factors for and lifestyle adjustments available to older adults. “All efforts to understand chronic disease are less effective because prenatal is not being addressed,” Thornburg says.
Thornburg’s current research aims to redress some of that gap, focusing on pregnant women and the influence of mothers’ diets on how babies grow. In Portland and Astoria, his researchers study and evaluate the placentas of women with various body types to better understand the link between the body, nutrition, fetal health, and infant health. Thornburg has also looked into how the health of pubescent girls is linked to breast and prostate cancer in their daughters and sons.
“I’m about 100 years old if we go back to the egg,” Thornburg says. Although the doctor’s hair is starkly white, 10 months plus his apparent age doesn’t add up to 100 years. He enjoys his visitor’s puzzled calculations, and delivers his punch line: “The egg that made me was made in my mother when she was a fetus in her mother’s womb.”
This simple concept—that the stuff that makes you existed in the bodies of your grandparents, and that their experiences affect how those genes manifest themselves in you—raises some profound questions. In January, Dr. Larry Wallack, an OHSU fellow, addressed an Oregon Legislature committee regarding Thornburg’s team’s work, in the hope that the research might eventually influence public health policies.
“When there’s a budget cut in Oregon, unfortunately women and children are first—to get cut,” Wallack says. He argues that we need to protect services for women and children because those services—especially when focused on the health of pregnant women and infants—can have far-reaching, even multigenerational impacts on the health of a community.
But even as chronic disease rates in Oregon continue to increase, Thornburg makes the bold claim that the research at OHSU and Portland State can do more than just reverse that trend: “We can look ahead to a time when chronic disease has been greatly reduced.”
Strong words, with proportional implications for how the health establishment tries to tackle the nation’s most prolific killers. Healthy eating campaigns, such as the ubiquitous billboards showing how much sugar is in soda, target short-term choices with known health benefits in a single lifetime. Focusing on the health and nutrition of young girls and boys, pregnant women, and the first 1,000 days of a child’s life, however, might foster much deeper changes, across generations.
Might. All of the data analyzed by Barker, Thornburg, and other epigenetics specialists does seem to show, again and again, that diet, environment, and social stress (such as war and poverty) in one generation correlate to the health of later generations. What we don’t know is whether there’s anything we can really do about that—whether intervening in one generation will help future offspring.
“Barker didn’t want to wait,” Wallack says. “He saw where the science was heading, and he knew the work was too urgent to wait.”
The interventions Barker advocated—a healthy diet; well-supported pregnancies—do no harm. But Thornburg remains circumspect about how quickly his research will lead to comprehensive change. “It takes a long time for science to develop a base of knowledge and translate that so that doctors understand it and use it in their practice,” he says.
Still, he is emphatic about the stakes. In public health, an upstream-downstream metaphor is often used to describe an approach to solving problems at the community level.
“We are often so busy pulling drowning people out of the river downstream that we don’t have time to go upstream, see what is causing them to fall in, and do something about it,” Wallack says. “This work is changing how far upstream we can go. And reminding us that we’re upstream right now for the next generation.”