Scientists Offer a New Twist on DNA

PHILADELPHIA – What makes you different from everyone else on the planet may have less to do with the spelling of your genetic code than with a scattering of chemical "tags" that, like censor’s marks, render some of your genes unreadable.

The code itself, after all, is 99.9 percent identical in all of us, so these peripheral elements – referred to as epigenetics — offer a plausible reason human beings come in such a variety of shapes and sizes.

As one recent paper suggested, epigenetics can explain why identical twins don’t always look identical, especially as they get older.

There’s a dynamic quality to epigenetics. Over your lifetime new chemical tags can stick to previously active genes, thus turning them off, while tags affixed from birth can occasionally fall off, activating genes that are meant to be disabled. A growing number of researchers are connecting such epigenetic shifts to cancer.

The good news is such changes are potentially reversible, says Frank Rauscher, a professor at the Wistar Institute. "For therapeutics, manipulating the epigenome is the way to go."

Unlike genetic mutations, which permanently scramble a cell’s genetic code, epigenetic tags leave the underlying code intact.

"The old dogma was that cancer was caused by DNA damage and gene mutations," says Jean-Pierre Issa, a researcher from the M.D. Anderson Cancer Center. But a closer look showed that cancer cells accumulate a combination of spelling errors in the DNA and inappropriate or missing epigenetic tags, he says. "This has led to a rethinking of environmental carcinogens and how diet could affect cancer and so on."

The most common tag that can get affixed to a gene is a so-called methyl group _ a carbon surrounded by hydrogen atoms. The genetic code is preserved beneath this, but it’s locked up, thus preventing the cellular machinery from carrying the gene’s instructions.

Methyl groups also shut down genes by attaching to proteins called histones that DNA wraps itself around.

"Having all these asterisks in your DNA is inherently very dangerous," says Peter Jones, a cancer researcher at the University of Southern California. For one thing, he says, epigenetic changes can disable critically protective genes called tumor suppressors. The only time these particular genes are supposed to be turned off, Jones says, is in early development in embryos.

In a paper published last month in Nature Genetics, Johns Hopkins researcher Steve Baylin and others found some similarities between cancer cells and embryonic stem cells. The embryonic cells temporarily disable their tumor suppressor genes in order to gain the power to generate all different cell types, he says. In adults, these genes are supposed to stay active, but occasionally in certain cells they get methylated again, a kind of reversion that makes them more prone to becoming cancerous.

USC’s Jones and others are figuring out how to fight back with drugs that strip off potentially dangerous methyl tags. Two such drugs were recently approved by the Food and Drug Administration for a myelodysplastic syndrome (MDS), a precursor to a virulent form of leukemia.

The drugs _ decitabine, by MGI Pharma, and azacitidine, by Pharmion Corp. _ don’t kill cancer cells the way standard chemotherapy agents do, says M.D. Anderson’s Issa, who has been involved in testing epigenetic therapies.

Instead, he says, the drugs re-educate cancer cells, making them behave more normally. "We’re trying to argue with them that they shouldn’t behave this way _ that they should stop growing," he said.

They may not cure the disease, he says, but in clinical trials they helped about a third of patients go into remission. "The patients have normal quality of life for a while."

Issa says he anticipates other drugs that work this way to follow.

At Fox Chase Cancer Center in Philadelphia, researcher Paul Cairns is using epigenetics for screening. "I work on the principle that cancers are present many years before they can be seen or cause pain or bleeding," he says. That gives doctors more time to intervene.

Early in the course of disease, he says, cancerous and precancerous cells start accumulating abnormal methylation, and these can show up in urine or blood tests.

Cairns and others funded through the National Cancer Institute’s Early Detection Program are developing urine tests to flag potential cases of bladder, kidney and prostate cancers and blood tests for breast and ovarian cancers. He and colleagues also found that epigenetic tests can pick up danger signs in otherwise negative prostate biopsies.

Unfortunately for us, we’re not only vulnerable to extra epigenetic tags, we can also lose tags we need _ ones that are supposed to stay fixed to cells from birth. At Johns Hopkins University, researcher Andrew Feinberg is looking at the consequences of such losses.

These fixed marks usually ride on just one of the two copies of each gene we carry _ either the one we get from our mothers or the one from our fathers.

For about 70 known genes, either the mother’s or father’s copy is permanently censored with epigenetics. Called imprinting, this process happens in all mammals. It explains, Feinberg says, why you get a mule when you cross a male donkey with a female horse but if you go the other way, you get a different-looking animal called a hinny.

Feinberg long suspected that imprinting played a role in cancer, and started seeking clues by studying Beckwith-Wiedemann syndrome, an often inherited disease that can lead to kidney cancer. Because it’s passed more often through mothers than fathers, scientists suspected it involved an imprinted gene.

In the late 1980s, Feinberg worked with geneticist Francis Collins to connect the disease to a piece of chromosome 11 that held several imprinted genes _ some with the father’s copy off and some with the mother’s off.

More recently, he’s found one of those genes, called IGF-3, also plays a role in colon cancer, he says. He compared colon cells from healthy people with those from cancer patients and found the latter much more likely to have cells that had lost their imprinting, activating a second copy of the gene.

He says he suspects the loss of imprinting puts the cells on a potential path to cancer. If any of them subsequently acquire certain genetic spelling errors, the combination of abnormalities fuels malignant growth. Eventually, he said, he hopes his findings could lead to tests for predicting and thereby preventing colon cancer.

Feinberg’s findings also raise a warning flag for drugs designed to strip off methyl tags, since they could possibly dislodge the critical methyl tags we’re supposed to have on our imprinted genes.

USC’s Peter Jones argues that we’ll gain a much better handle on cancer and stem cell research if we take time to unlock the secrets of these epigenetic tags systematically. So he has proposed a human epigenome project as a follow-up to the 1990s push to map the human genome.

Others say the epigenome represents a natural next step _ but a daunting one, since there’s a different one for every type of cell we carry. The current frontier is comparing the genetic codes, or genomes, of different species, says Wistar’s Rauscher.

"The next frontier is finding the epigenome."