In a word, Michael Skinner is tenacious. Growing up on a ranch outside Pendleton, the former Eagle Scout and college wrestler learned early on that you don’t back down from a little head-butting or controversy. It’s all just part of the game.
The trait has served Skinner ’82 PhD well over the years and enabled him to persevere through the fallout of a chance discovery in his reproductive biology lab in the 1990s. The unexpected findings threw 200 years of scientific ideology into question and initiated a paradigm shift in the understanding of inheritance and evolution. They also sparked a wave of outrage and debate that continues today.
The Washington State University Eastlick distinguished professor and founding director of the Center for Reproductive Biology was the first to clearly document a nongenetic form of inheritance that works through epigenetics. The epigenome—which means “on genetics”—is a suite of chemical molecules that attach to DNA and regulate gene function like tiny on-and-off switches.
Skinner showed that certain agricultural and manufacturing chemicals can alter the epigenome in pregnant rats and those alterations subsequently passed down for four generations without changes to the underlying DNA. These epigenetic changes were also linked to a disturbing increase in disease in the rat’s grandchildren and great-grandchildren.
In effect,“environmental contaminants dramatically change gene expression in the offspring without causing mutations in the DNA,” says Skinner. “These are things that don’t fit the traditional genetic paradigm.”
The implications are huge. “What your great-grandmother was exposed to in her environment might actually influence what disease you’re going to get and might also pass onto your grandchildren,” he says.
Since the 1940s, it’s been generally accepted that the DNA sequence controls transfer of biological information from one generation to the next. To suggest that environment alone could change heritable traits upended models stretching back to the battle between Darwin and Lamarck in the 1850s.
Skinner is well aware. “We’re challenging the chief paradigm in biology—genetic determinism—which suggests that your DNA sequence determines your destiny. I believe genetics is only a small piece of a much bigger story. Environmental epigenetics is probably equally important in regards to inheritance, disease etiology, or evolution.”
The idea of nongenetic inheritance had been bandied about by academics in the past but Skinner’s breakthrough provided the first plausible mechanism by which it could occur.
His inaugural publication on the topic in 2005 ignited a scientific firestorm that thrust him into the spotlight as a leader in the new field of transgenerational epigenetics—the study of inherited changes that can’t be explained by traditional genetics.
Along with it came the dawning realization that supposedly harmless chemicals, stress, or nutritional deficits could in fact impart health problems to later generations. The bad news was somewhat tempered by a silver lining—the discovery also gave medical researchers new opportunities to improve personalized medicine and the diagnosis and treatment of disease.
In 2013, Skinner was honored with a Smithsonian American Ingenuity Award, given annually to people having a revolutionary effect on their fields.
Though some still doubt his findings and even regard him as a heretic, Skinner says hundreds of similar papers involving epigenetics in plant and animal species are being published each year.
“These paradigm shifts in science always take at least a generation to occur,” he says. “It takes a new generation of scientists with no vested interests to get involved and carry it forward.”
A NUMBER OF THESE YOUNG SCIENTISTS cut their teeth on microscopes and dissecting trays in the classrooms of historic Abelson Hall on the WSU Pullman campus.
Up five flights of stairs in the stalwart building, you’ll find the Skinner Laboratory, a quiet work space filled with hundreds of bottles arranged neatly on clean shelves, the tile floors surprisingly waxed and shiny.
In the back, the professor welcomes visitors into his office where an enormous northern pike appears to leap from the wall to greet them. The avid outdoorsman is casual in jeans and a gray wool shirt. His Stetson fedora rests in its spot on the bookshelf.
“The story began in the late 1990s,” Skinner says as he reaches for a Starbucks coffee cup and leans back in his chair.
“I was studying the effects of two widely-used farming chemicals on pregnant rats—the pesticide methoxychlor and a fungicide called vinclozolin,” he says. “Like many agricultural chemicals, the two are known to be endocrine disruptors that can interfere with normal development and function of the reproduction system.”
In this experiment, one of Skinner’s postdoctoral fellows, Andrea Cupp, exposed the rats to methoxychlor during the time the fetal tissues were developing into ovaries and testes. They wanted to see if it would affect sex determination in the pups.
“Unfortunately, it was a failed experiment,” Skinner says. “There was no obvious impact on sex determination.”
When the pups grew up, however, they discovered that 90 percent of the male offspring had abnormal testes and most of the sperm were dying. Those that did survive were much weaker than normal. Skinner and Cupp dutifully recorded the results and moved on to other projects.
Then, one day, Cupp knocked on Skinner’s door offering apologies. “She was upset as she had accidentally bred the unrelated male and female pups from the methoxychlor experiment,” he says.
“I said, ‘don’t worry about it. Just go ahead and look at the testes in the grandpups.’ Since toxicology studies had not shown methoxychlor to cause these kinds of DNA mutations, I didn’t expect to find any defects.”
“A month later she came back and reported the exact same changes as in the others,” says Skinner. “More than 90 percent of the males had very high levels of sperm cell death even though their parents were just tiny fetuses when their grandmothers were briefly exposed.”
Surprised, the researchers checked the rat’s DNA and confirmed that there were no new genetic mutations. Skinner also knew that a new trait appearing with 90 percent frequency in different families could not be explained by classical genetics. The traits should decline over time.
“So, of course, I didn’t believe Andrea’s findings,” he says.
What happened next is described by Skinner in excerpts from a detailed account he penned for Scientific American in 2014:
There was one sure way to find out whether the chemicals were to blame. I asked Andrea to breed a fourth and then fifth generation, each time mating unrelated descendants of the original exposed rats. As the great-grandchildren—and later, the great-great-grandchildren—matured, the males all suffered problems similar to those of their ancestors. All these changes stemmed from a fleeting but very high dose of agricultural chemicals that for decades have been sprayed on fruits, vegetables, vineyards, and golf courses.
“I was shocked by these results,” says Skinner. “Over several years, we repeated the experiments multiple times to confirm them and collect additional evidence. It was obvious it could not be genetics and the only other mechanism known was epigenetics.
The most plausible explanation, we concluded, was that the exposure causes a mutation in the epigenome that interferes with gonad development in male embryos—and this epimutation passes from sperm to the developing embryo, including its primordial germ cells, for generations.
“So, it was a very serendipitous observation from a mistake in the lab that led us down the path and into the field of epigenetics,” says Skinner. “But we’ve known for a long time that major scientific advances are often serendipitous observations that someone goes on to investigate. Pasteur, for example, had no concept for antibiotics before he made his observation that led to the discovery of penicillin.”
Despite the team’s excitement, Skinner didn’t immediately inform the scientific community.
“I sat on the observation for five years until we had enough evidence to convince ourselves it was actually epigenetics,” he says. “It was critical to sit on it until we had the mechanism, since the concept of nongenetic inheritance had been suppressed for nearly 200 years. It was heresy to propose something like this 10 years ago.”
In 2000, Cupp left for a job at the University of Nebraska-Lincoln where today she oversees her own reproductive biology lab as a professor and chair of animal science.
In time, Skinner and his colleagues pinpointed several spots in sperm DNA where the epigenome had been altered by the chemicals. New methyl molecules were attached to some of the genes and these “methylation tags or marks” damaged sperm production.
“Once we had the mechanism nailed down, we published the 2005 paper on transgenerational epigenetics,” he says.
“Putting it out there was a big deal. It advances our understanding that we’re not just inheriting our DNA sequence, we are inheriting our epigenetics. And since the environment can dramatically alter epigenetics, suddenly the environmental impact on inheritance is important. Before, it wasn’t.”
THE UPROAR WAS IMMEDIATE
The first significant pushback came from his fellow academicians, the molecular biologists. Looking back, Skinner says, “It’s probably routine, in a major discovery, that the institutional opposition usually develops first. Their life’s work is being challenged—I understand why they opposed it.”
The agro-chemical companies also rebelled. With their bottom line at stake, industry researchers were skeptical when they could not initially reproduce some of Skinner’s findings. The discrepancy was likely due to using different experimental methods and was later resolved, Skinner says.
Government toxicologists who set FDA and EPA standards for drug and chemical use were no happier and balked at implications that their testing methods were incomplete or inaccurate.
Skinner explains that in the field of toxicology, scientists use direct exposure to assess whether a compound is harmful or not. These tests then determine how a chemical is regulated for public use.
“The problem is, many of the chemicals I tested in my lab had no direct toxic effects on the exposed rat or her pups, but there was a very dramatic increase in disease in the great-grandpups,” he says. “So, in my mind, we can’t just look at a person who is exposed; we also need to do toxicology studies for up to three generations to determine if there will be any effects.”
The controversy softened a bit after Skinner published a half dozen new papers further confirming that epigenetic changes can persist for several generations. Eventually, some of his opponents investigated for themselves and published their own findings.
“The anger comes in waves,” Skinner says. “Industry, academics, government agencies, and commodities groups—they ebb and flow as to which one is currently active. But, it’s my motto that if you’re not doing something controversial, you’re not doing something important.”
In 2012, Skinner again rattled the status quo when he challenged the notion of Darwinian evolution.
“We started getting into evolution because if epigenetics is critical, it has to be critical for everything,” he says. “A lot of evolutionary components can’t be explained with genetics alone—they tried but it doesn’t fit.”
The current paradigm was established around 1850 when Darwin proposed the concept of natural selection which states that environmental forces select for individuals with the most adaptive genetic traits.
“Darwin was absolutely correct that natural selection is one major driver for the process of evolution,” Skinner says, “But there is more to the story.”
He refers to a lesser-known naturalist named Jean-Baptiste Lamarck who, in 1802, speculated that environment could directly alter physical traits and those acquired traits then passed on to children and grandchildren. The classic example is the elongated neck of the giraffe, which Lamarck said could’ve been produced through years of straining to reach tall branches. His theory was eventually rejected in favor of Darwin’s.
Skinner, who has a soft spot for the underdog, says environmental epigenetics now provides the molecular evidence showing that Lamarck was correct in this aspect of his hypothesis.
“Environment does have the ability to increase variation in your traits through epigenetics,” he says.
“Furthermore, our studies show that epigenetic changes can increase susceptibility for all types of genetic mutations. So, genetic variation can come from environmental epigenetics.”
Skinner pauses for a moment. “I want to be very clear here,” he begins. “I’m not saying anything against genetics. Genetics is absolutely essential. But there will never be a genetic-only process and there will never be an epigenetic-only process. These two things are integrated and cannot be separated.”
He first took this “unified theory of evolution” public at the University of Wisconsin-Madison, an institution known for its scholarly evolution department. Skinner says he was curious as to how they would receive him.
It didn’t take long to find out. Three times during the presentation, seasoned faculty members stood up and loudly interrupted him.
“It’s extremely well established that genetics is the primary molecular mechanism for evolution and is supported by studies for decades, so why suggest anything else?” one shouted.
Reflecting back, Skinner says, “It was somewhat expected as science investigators spend 30–40 years studying a specific paradigm. Then some guy comes along and says it’s not that this is wrong, but we need to add other parts. So, for some well-established scientists, there’s a knee-jerk reaction against that kind of thing. It’s just human nature.”
“Today I could go there with no problems; this was their first time hearing about it and it shocked them,” he says. “But then they sit back and think about it. They look in the literature and realize that many people are starting to investigate this area. So, it’s slowly changing.”
He gives a little laugh. “I didn’t know it, but this also happened to be Darwin Week at the university. As soon as I said the word Lamarck, there was controversy.”
SINCE THAT DAY, Skinner and other scientists have observed transgenerational inheritance of acquired characteristics in a wide range of species, including plants, flies, worms, fish, birds, rodents, and pigs. And with that comes disease susceptibility that individuals might not otherwise have.
“Today, no one doubts that epigenetic effects play a crucial role in development, aging, and even cancer,” Skinner writes in Scientific American. “Follow-up studies at my lab have shown that the great-grandchildren of vinclozolin-treated rats have consistently altered patterns of methylation in their sperm, testes, and ovaries, as well as abnormal gene activity in their primordial germ cells. We also found that fourth-generation offspring are prone to weight gain and anxiety; they even select mates differently.”
Skinner says almost anything in the environment can cause these epigenetic changes, beginning with the food we eat each day.
“There are thousands of compounds in plants that we’ve adjusted to over the centuries. Genistein, for example, is a compound in soy that decreases the risk of prostate disease and is known to be modulated by epigenetics. Starvation and high-fat diets also alter the epigenome.”
Stress at critical points in development can likewise trigger changes as can the hundreds of chemicals we are exposed to every day in our industrial society. A number of these compounds have been investigated in Skinner’s lab where the workload relies heavily on the talents of postdoctoral fellows and select undergraduate students whom he recruits as freshmen.
One of those freshmen students was Margaux McBirney ’17 who was recently listed as first author on a PLOS One publication showing that atrazine, an herbicide commonly used on soy and corn, causes epigenetic effects. Though it had no direct effects on exposed rats or their pups, she helped demonstrate that 80-90 percent of the grandpups and great-grandpups suffered from more than one disease, including the inability to store fat.
“It’s amazing that Dr. Skinner gives opportunities with these kinds of responsibilities to undergraduates,” says McBirney, who is now a research technician at the Fred Hutchinson Cancer Research Center in Seattle.
Over the years, Skinner’s team has also confirmed epigenetic health risks from Bisphenol A and phthalates in plastics, jet fuel, dioxin, permethrin, mercury, and DEET, as well as DDT and methoxychlor, which both promote obesity.
He says body tissues are most susceptible to environmental insults during times of rapid growth and development. Some organs like the mammary gland, prostate, testis, ovary, kidney, adipose tissue, and brain are sensitive to small epigenetic shifts while muscle, liver, and bone can withstand larger shifts with fewer problems.
“It turns out, there’s not really too much we can do about it, so this is pretty doom and gloom,” Skinner says. “Once methyl tags are programmed in the germ line, we don’t know of a way to prevent it. Yet, by simply knowing this phenomenon exists, it will allow us in the future to both prevent and treat diseases.”
Methyl tags do not always lead to disease, however. Skinner says your environment likely determines whether a susceptibility will go on to manifest as illness. The first line of defense is to adopt a healthy lifestyle and diet. Avoiding chemicals, maximizing exercise, and eating nutritious food could help deter or postpone disease onset.
“We used to think you were programmed to get a disease if you had a certain gene mutation, and no matter what you did, you’d get it. But that’s clearly not the case,” he says.
“Genome-wide association studies show that generally less than one percent of any disease has an associated genetic mutation. This suggests that the majority of diseases are not related to genetic mutations.
“In our studies, 90 percent of animals with a disease have epigenetic shifts. So, clearly things like the environment have been overlooked as potential causes of disease.”
Looking toward the future, Skinner says he’ll continue to unravel the precise mechanics of the transgenerational epigenetic process. He and his team are also breaking ground in the discovery of new diagnostic tests for the medical field.
“Theoretically, we should be able to do an epigenome analysis in our early twenties and determine if we have a susceptibility to various diseases,” Skinner says. “And if so, we can be prescribed a lifestyle or diet or therapeutic change to prevent it from developing.
“So, I think preventative medicine will become a reality not because of genetics but of epigenetics. We may not be able to fix it but we will potentially be able to treat it.”
View the full size infographic (PDF)
Read more: “Another look at Darwin’s finches.”
Web extra
Video: Ancestral ghosts in your genome
A TEDxRainier presentation by Washington State University biologist Michael Skinner