Shifting the Genetic Paradigm with Epigenetics

Michael Skinner hopes his research will lead to medical tests that could determine which environmental factors our ancestors might have been exposed to. | Washington State University

Biologist Michael Skinner isn’t one to shy away from a good fight. In fact, prominently displayed on his webpage are the words: “If you are not doing something controversial, you are not doing something important.”

A rebel by nature, the 60-year-old AAAS Fellow is fond of quoting Thomas Kuhn, best known for his treatise describing how scientific beliefs—called paradigms—are established and then torn down. For the last decade, Skinner has been tearing down biology’s bedrock, its paradigm par excellence: genetic determinism, the idea that DNA is destiny.

“Genetic determinism is part of the story, but it’s not the whole story. It turns out the environment has a major impact on biology,” says Skinner.

For over a century, it has been believed that genetic inheritance is the factor in determining life’s many forms, including disease. Skinner and his team of researchers at his Washington State University lab are part of a vanguard documenting important exceptions to this powerful rule.

Skinner studies epigenetics, or molecular factors that regulate how DNA functions, including what genes get turned on and off. His research has demonstrated that traits can be passed from generation to generation epigenetically, that is without producing genetic mutations.

Focusing on environmental toxicants, Skinner’s work, and its implications for evolutionary biology, has earned him enemies in the chemical industry as well as the scientific community. But Skinner’s career began much more peacefully.

Skinner’s current home in Pullman, Washington—a small college town in a rural setting—is similar to where he grew up in eastern Oregon. A nature lover, sometimes hunter, and longtime fisherman, Skinner, who's fond of Indian Jones–style Stetson hats, looks more rancher than lab-coated scientist. He says it was his love of the outdoors that inspired his love of science.

He began his scientific career in the early 1980s studying reproductive cell biology with a focus on how cells communicate with each other and how the endocrine system—that network of glands and hormones—regulates the whole process.

From studying healthy endocrine systems in rats (his preferred animal model) it was a no-brainer to move on to factors that throw the endocrine system out of whack, he says. Starting in the early 1990s, Skinner turned his eye to troublemaking endocrine disruptors. 

Ranging from chemicals found in plastics, including the now infamous BPA (Bisphenol A), to the equally infamous insecticide DDT (made famous by Rachel Carson in Silent Spring), endocrine disruptors have been implicated in everything from birth defects to cancer. Wanting to understand how sex determination could be affected by endocrine disruption, Skinner and colleagues exposed a gestating female rat to vinclozolin, a popular fungicide.

The results were a dud: no effect on sex determination in the initial offspring, the “F1” generation. However, the researchers did note that 90 percent of the F1 generation males showed an abnormality in their testes. That’s where things might have ended had Skinner’s postdoc not accidentally bred the F1 rats with normal lab rats. Curious, and hoping to calm his colleague upset over her mistake, Skinner asked her to examine the resulting “F2” generation. To their surprise, 90 percent of the males in that generation had the same testicular abnormality, the same as before.

“Of course I didn’t believe her. So I had her run the experiment another 15 times—and that’s not an exaggeration,” says Skinner.

As generation after generation showed the same abnormally at the same rate, Skinner says it became clear that they were dealing with an inherited trait. But there was a catch. Vinclozolin was not a mutagen, meaning the changes they were seeing were not the result of genetic changes. Also puzzling was how the trait was consistently showing up in 90 percent of the male rats. With genetically heritable traits, each subsequent generation shows a decline in frequency, becoming diluted over time.

“This led us to the conclusion that we were probably looking at an epigenetic factor and that this was a form of nongenetic inheritance, which was utter heresy,” says Skinner.  

Worried about how their results would be received, Skinner sat on his data for years, giving himself time to run multiple experiments. This also gave him and his colleagues time to track down the epigenetic factor at work. Finally, they published their results in Science in June 2005.

The epigenetic factor they identified was DNA methylation, a natural molecule process involved in turning genes on and off that appeared to get hijacked by vinclozolin. Since their initial findings, Skinner and his team have examined other environmental factors. This work has revealed that multiple compounds can produce inheritable epigenetic traits manifesting as diseases and abnormalities. He also discovered that compounds did so in unique ways and with no overlap, effectively fingerprinting which compound a given rat had been exposed to. 

In the future, Skinner hopes this research will lead to medical tests that could determine which environmental factors our ancestors might have been exposed to, giving us a tool to diagnose and treat diseases we might develop. To date, his work is still only theory; however, a series a “natural experiments” in humans, mostly well-documented historical famines, have been shown to produce epigenetic inheritance in humans.

In the meantime, Skinner has set his sights on evolutionary biology. This work has further demonstrated that individuals can pass on traits obtained in their lifetimes to their offspring. As for his role in breaking up the paradigm of genetic determinism, he wants to see more of that kind of disruption in science.

“What if our primary motive in science wasn’t to build up a paradigm, but to tear it down? If we actually had that level of controversy being generated, the progression of science would be significant,” says Skinner.