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Epigenetics research takes aim at cancer, Alzheimer's, autism, other illnesses

http://www.washingtonpost.com/wp-dyn/content/article/2009/12/14/AR2009121402894.html

Research on mice might have meaning for many human illnesses

By Rachel Saslow, Washington Post Staff Writer, Tuesday, December 15, 2009; HE05

Two mice. One weighs 20 grams and has brown fur. The other is a hefty 60 grams with yellow fur and is prone to diabetes and cancer. They're identical twins, with identical DNA.

So what accounts for the differences?

It turns out that their varying traits are controlled by a mediator between nature and nurture known as epigenetics. A group of molecules that sit atop our DNA, the epigenome (which means "above the genome") tells genes when to turn on and off. Duke University's Randy Jirtle made one of the mice brown and one yellow by altering their epigenetics in utero through diet. The mother of the brown, thin mouse was given a dietary supplement of folic acid, vitamin B12 and other nutrients while pregnant, and the mother of the obese mouse was not. (Though the mice had different mothers, they're genetically identical as a result of inbreeding.) The supplement "turned off" the agouti gene, which gives mice yellow coats and insatiable appetites.

"If you look at these animals and realize they're genetically identical but at 100 days old some of them are yellow, obese and have diabetes and you don't appreciate the importance of epigenetics in disease, there's frankly no hope for you," Jirtle says.

He offers this analogy: The genome is a computer's hardware, and the epigenome is the software that tells it what to do.

Epigenomes vary greatly among species, Jirtle explains, so we cannot assume that obesity in humans is preventable with prenatal vitamins. But his experiment is part of a growing body of research that has some scientists rethinking humans' genetic destinies. Is our hereditary fate -- bipolar disorder or cancer at age 70, for example -- sealed upon the formation of our double helices, or are there things we can do to change it? Are we recipients of our DNA, or caretakers of it?

Last year, the National Institutes of Health announced that it would invest $190 million to accelerate epigenetic research. The list of illnesses to be studied in the resulting grants reveals the scope of the emerging field: cancer, Alzheimer's disease, autism, bipolar disorder, schizophrenia, asthma, kidney disease, glaucoma, muscular dystrophy and more.

When Jirtle planned his first epigenetics conference in 1998 in Raleigh, N.C., epigenetics was such a small field that he worried nobody would come. About 160 people attended. Jirtle hosted another conference in 2005; it attracted 470.

"It's the flavor of the month," says Michael Meaney, a brain researcher at McGill University in Montreal.

When a gene is turned off epigenetically, the DNA has usually been "methylated." Biologists have known for decades that methylation is involved in cell differentiation in utero, making one cell a skin cell, another cell a liver cell, and so on. Cell differentiation is also what happens when scientists prompt an embryonic stem cell to grow into a specific type of cell. But five years ago, when Meaney submitted a paper suggesting that DNA methylation happens throughout life in response to environmental changes, he was told, "This just can't happen." (Most DNA methylation occurs prenatally and during infancy, puberty and old age, Jirtle says. Research suggests that epigenetically, humans are pretty stable during adulthood.)

Duke Department of Medicine researcher Simon Gregory described the link between DNA methylation and autism in a paper published in October in the journal BMC Medicine.

Most genetic studies of autism focus on variations in the DNA sequence itself, especially on genes that are missing. Gregory and his colleagues looked at an oxytocin receptor gene, called OXTR, and found that about 70 percent of the 119 autistic people in his study had a methylated OXTR; in a control group of people without autism, the rate was about 40 percent. Oxytocin is a hormone that affects social interaction; difficulty relating to others is common for those with autism spectrum disorders.

Because this was only a pilot study, more research is necessary. But Gregory says methylation-modifying drugs might be a new avenue for treatments. He also hopes that his findings will provide a new tool for doctors to diagnose autism.

"Methylation has been very hot in the cancer field for a number of years," Gregory says. "To find something like this associated with autism is very exciting."

Epigenetic therapy is still very inexact -- "a pretty broad brush," says Jirtle. But oncologists have seen some success in using it against leukemia. Azacitidine, sold as Vidaza and used to treat bone-marrow cancer and blood disorders, became the first FDA-approved epigenetic drug in 2004. When tumor-suppressing genes aren't doing their job, due to a genetic mutation or hypermethylation, cancer cells can replicate uncontrollably. But by manipulating the epigenetic marks, doctors can get tumor-suppressing genes to work again. Toxicologists also have a big stake in epigenetics. A 2005 study by Washington State University molecular biologist Michael Skinner generated buzz with his finding that when a pregnant rat was exposed to high doses of pesticides, her offspring plus the next three generations suffered from high rates of infertility. (Some scientists have challenged Skinner's work because they have not been able to reproduce his results in their labs.)

The potential human implications -- do the chemicals we ingest today affect our great-grandchildren? -- are tremendous. In addition to pesticides, toxicologists are studying chemicals in plastics, such as phthalates and bisphenol A, to see if they could enhance our risk of disease by altering the epigenome.

Jirtle says that he and his fellow researchers usually discuss epigenetics only on the microscopic level, but when he pulls back and looks at the big picture, he is awed.

"I've got goose bumps right now talking about it," he says. "You're looking at the book of life, how it's read and how you can change it."