"People used to think that once your epigenetic code was laid down in early development, that was it for life," says Moshe Szyf, a pharmacologist with a bustling lab at McGill University in Montreal. "But life is changing all the time, and the epigenetic code that controls your DNA is turning out to be the mechanism through which we change along with it. Epigenetics tells us that little things in life can have an effect of great magnitude."
Szyf has been a pioneer in linking epigenetic changes to the development of diseases. He long ago championed the idea that epigenetic patterns can shift through life and that those changes are important in the establishment and spread of cancer. For 15 years, however, he had little luck convincing his colleagues. One of his papers was dismissed by a reviewer as a "misguided attempt at scientific humor." On another occasion, a prominent scientist took him aside and told him bluntly, "Let me be clear: Cancer is genetic in origin, not epigenetic."
Despite such opposition, Szyf and other researchers have persevered. Through numerous studies, Szyf has found that common signaling pathways known to lead to cancerous tumors also activate the DNA-methylation machinery; knocking out one of the enzymes in that pathway prevents the tumors from developing. When genes that typically act to suppress tumors are methylated, the tumors metastasize. Likewise, when genes that typically promote tumor growth are demethylated—that is, the dimmer switches that are normally present are removed—those genes kick into action and cause tumors to grow.
Szyf is now far from alone in the field. Other researchers have identified dozens of genes, all related to the growth and spread of cancer, that become over- or undermethylated when the disease gets under way. The bacteria Helicobacter, believed to be a cause of stomach cancer, has been shown to trigger potentially cancer-inducing epigenetic changes in gut cells. Abnormal methylation patterns have been found in many cancers of the colon, stomach, cervix, prostate, thyroid, and breast.
Szyf views the link between epigenetics and cancer with a hopeful eye. Unlike genetic mutations, epigenetic changes are potentially reversible. A mutated gene is unlikely to mutate back to normal; the only recourse is to kill or cut out all the cells carrying the defective code. But a gene with a defective methylation pattern might very well be encouraged to reestablish a healthy pattern and continue to function. Already one epigenetic drug, 5-azacytidine, has been approved by the Food and Drug Administration for use against myelodysplastic syndrome, also known as preleukemia or smoldering leukemia. At least eight other epigenetic drugs are currently in different stages of development or human trials.
 To the surprise of scientists, many environmentally induced changes turn out to be heritable. When exposed to predators, Daphnia water fleas grow defensive spines (right). The effect can last for several generations. |
Other researchers are focusing on how people might maintain the integrity of their epigenomes through diet. Baylor College of Medicine obstetrician and geneticist Ignatia Van den Veyver suggests that once we understand the connection between our epigenome and diseases like cancer, lifelong "methylation diets" may be the trick to staying healthy. Such diets, she says, could be tailored to an individual's genetic makeup, as well as to their exposure to toxins or cancer-causing agents.
In 2003 biologist Ming Zhu Fang and her colleagues at Rutgers University published a paper in the journal Cancer Research on the epigenetic effects of green tea. In animal studies, green tea prevented the growth of cancers in several organs. Fang found that epigallocatechin-3-gallate (EGCG), the major polyphenol from green tea, can prevent deleterious methylation dimmer switches from landing on (and shutting down) certain cancer-fighting genes. The researchers described the study as the first to demonstrate that a consumer product can inhibit DNA methylation. Fang and her colleagues have since gone on to show that genistein and other compounds in soy show similar epigenetic effects.
Meanwhile, epigenetic researchers around the globe are rallying behind the idea of a human epigenome project, which would aim to map our entire epigenome. The Human Genome Project, which sequenced the 3 billion pairs of nucleotide bases in human DNA, was a piece of cake in comparison: Epigenetic markers and patterns are different in every tissue type in the human body and also change over time. "The epigenome project is much more difficult than the Human Genome Project," Jirtle says. "A single individual doesn't have one epigenome but a multitude of them."
Research centers in Japan, Europe, and the United States have all begun individual pilot studies to assess the difficulty of such a project. The early signs are encouraging. In June, the European Human Epigenome Project released its data on epigenetic patterns of three human chromosomes. A recent flurry of conferences have forwarded the idea of creating an international epigenome project that could centralize the data, set goals for different groups, and standardize the technology for decoding epigenetic patterns.
Until recently, the idea that your environment might change your heredity without changing a gene sequence was scientific heresy. Everyday influences—the weights Dad lifts to make himself muscle-bound, the diet regimen Mom follows to lose pounds—don't produce stronger or slimmer progeny, because those changes don't affect the germ cells involved in making children. Even after the principles of epigenetics came to light, it was believed that methylation marks and other epigenetic changes to a parent's DNA were lost during the process of cell division that generates eggs and sperm and that only the gene sequence remained. In effect, it was thought, germ cells wiped the slate clean for the next generation.
That turns out not to be the case. In 1999 biologist Emma Whitelaw, now at the Queensland Institute of Medical Research in Australia, demonstrated that epigenetic marks could be passed from one generation of mammals to the next. (The phenomenon had already been demonstrated in plants and yeast.) Like Jirtle and Waterland in 2003, Whitelaw focused on the agouti gene in mice, but the implications of her experiment span the animal kingdoms.
"It changes the way we think about information transfer across generations," Whitelaw says. "The mind-set at the moment is that the information we inherit from our parents is in the form of DNA. Our experiment demonstrates that it's more than just DNA you inherit. In a sense that's obvious, because what we inherit from our parents are chromosomes, and chromosomes are only 50 percent DNA. The other 50 percent is made up of protein molecules, and these proteins carry the epigenetic marks and information."
