Emerging science aims to manipulate human DNA

[Guest guest]

Research on mice might have meaning for many human illnesses

By Saslow

Washington Post Staff Writer

Tuesday, December 15, 2009

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 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 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. 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

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, "

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 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. "