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Genetics’ accomplice: Emerging field of epigenetics hints at new culprits in disease

By Sue Goetnick Ambrose, Dallas Morning News

2 November 2003: After scientists decoded the human genetic blueprint, the mysteries of disease were supposed to be simpler to solve.

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But researchers are starting to warn that the genetic blueprint has extra text that's only beginning to emerge. Solving some disease mysteries, they say, won't happen until this extra information is fully understood.

Scientists already know this extra layer of information commands cancer cells to flourish. Now there's speculation that it might be at the root of autism or other neurological disorders, or even account for certain birth defects in test-tube babies.

This extra information could also solve some genetic brainteasers, such as why "identical" twins aren't always identical or how your grandparent's diet can land you in the hospital.

Techniques to study this add-on to the genetic code are still emerging. But as tools improve, researchers anticipate revelations about disease and a new frontier for medicine.

"I think," said David Allis, a molecular biologist at Rockefeller University in New York City, "this is going to creep into every aspect of biology."

Scientists refer to the extra layer of information as "epigenetic" – outside ordinary genetic inheritance. Basic hereditary information is spelled out in long chains of DNA letters that make up an organism's genetic blueprint. Cataloging the human genetic blueprint, or genome, took more than a decade, and has already given insights into why some people get sick and others stay healthy.

Epigenetic information embellishes the blueprint

Instead of existing as a bare set of instructions, researchers have found, the genetic blueprint is studded in special places with chemical flags that designate whether or not a gene should be activated. Portions of the blueprint are also wrapped in different ways as another type of on/off signal. In other cases, small pieces of DNA's molecular cousin, RNA, settle in certain places on the blueprint to remind a cell to keep that area quiet.

Sometimes this extra biological information is passed from parent to child and sometimes it isn't.

"What we inherit from our parents is not naked DNA," said Dr. Arturas Petronis, a researcher at the Centre for Addiction and Mental Health in Toronto. "Those epigenetic signals can be transmitted from one generation to the next."

For years, hints that epigenetic information can wield great power have been scattered throughout the medical literature. Experiments have shown that epigenetics drives cancer and hinders attempts to clone animals. That work is leading researchers to wonder whether epigenetics reaches into other aspects of human biology.

Chemical safety

Some scientists speculate that autism, schizophrenia, bipolar disorder and other diseases may reflect epigenetics in action. And if epigenetics is so important in spurring cancer, experts say, perhaps safety tests of chemicals should check not only for damage to genes but also for epigenetic insults to the genetic code. Likewise, nutritionists are starting to suspect that diet can alter epigenetic information passed on to future generations. "All we have at this point is a theory," said Petronis. "We still have a long way to go, and maybe we are wrong. But ... we can explain a lot of findings ... and can suggest some critical experiments that can tell us whether this theory is correct."

This emerging epigenetic theory rests upon the basic facts of heredity. Virtually each cell in the body contains two copies of the genome, one inherited from each parent. Cells constantly refer to this DNA instruction manual to make proteins and other molecules that keep the body up and running.

Sometimes tiny misspellings or longer gaps in the DNA code cause disease. These errors can be passed on from parent to child, explaining why conditions such as cystic fibrosis or color blindness are inherited. Spelling differences in the DNA code, scientists say, also explain people's varied sizes, shapes and colors.

But typos and garbled syntax are not the whole story, geneticists now say. Identical stretches of DNA can give a cell dramatically different instructions, depending on how the epigenetic information has annotated the genetic code.

"It's like peeling layers off the onion," said Randy Jirtle, a molecular biologist at Duke University Medical Center in Durham, N.C. "This is another layer of control" in the bureaucracy cells have established just to read their own DNA.

Accidents and changes happen in the epigenetic layer, too. Even if researchers don't know why epigenetic information gets perturbed, the fact that it's not foolproof may explain a lot.

For instance, in recent years, scientists have spent millions of research dollars hunting for DNA misspellings that might be responsible for schizophrenia, bipolar disorder, diabetes, asthma and other diseases. So far, these hunts have turned up few culprits.

Missing the genes

Most scientists believe the gene hunts have been difficult because there are so many misspelled genes working together, making any one gene hard to find. But equally possible, some researchers say, is that just one gene or a few genes are at the heart of these diseases, and the epigenetic information attached to them varies from person to person. Studies that focus on DNA misspellings might miss those genes.

Geneticists have also been unable to explain why identical twins sometimes aren't. Born of the same egg and sperm, the twins' genetic blueprints couldn't be more similar. Yet physicians have known for decades that one twin can become chronically ill while the other carries on in perfect health. If one identical twin is autistic, for example, the other often is, too, but only in 60 percent of the cases. For people with schizophrenia and bipolar disorder, two debilitating mental illnesses, the rate for their identical twins hovers near 50 and 75 percent.

Doctors have explained this twin paradox by saying something in the environment – a virus, say, or stress – triggers disease in one twin but not the other. But decades of searching hasn't turned up convincing triggers.

Enter epigenetics. What if, scientists are asking, chemical flags settle on one twin's DNA but not the other's? If these flags are sprinkled on or stripped from a gene that's critical for brain development, could autism or schizophrenia develop?

"Pediatricians will call me and say this is cool," said Rockefeller's David Allis. "One identical twin will be hugely normal and the other will be hugely autistic. What gives? The biology tells us that the kids are really genetically matched sets."

There's still no proof that epigenetics is behind identical twins' differences. But it's such a logical explanation, researchers argue, it's worth investigating.

A recent study by Petronis and colleagues, for example, shows that genetically identical twins can differ epigenetically. This year in Schizophrenia Bulletin, the scientists reported on a study of two pairs of identical twins. In one pair, both twins had schizophrenia. In the other pair, only one did.

Epigenetically unique

The scientists scrutinized the epigenetic flags on a gene implicated in schizophrenia. In the pair who both had the disease, the scientists noted similar epigenetic patterns. In the other pair, the twin who had schizophrenia was epigenetically more similar to the first pair than to the sibling. It could be that the "sick" epigenetic pattern is contributing to schizophrenia, Petronis said. Even if that's not the case, he said, the study shows that two people who are genetically matched can be epigenetically unique.

Not all scientists are sold on epigenetics as the solution to mankind's puzzling ailments. Effects of the environment on disease are understudied, said Steve McKnight, chairman of biochemistry at the University of Texas Southwestern Medical Center at Dallas.

"It's reasonable for people to think about epigenetic phenomena to explain these diseases, but it wouldn't be the first thing I'd turn to," McKnight said. "I'd think that environmentally or developmentally something happens that opens the window."

Nevertheless, McKnight said, epigenetics is showing up so often that it's hard to ignore.

In the past few years, more and more medical conferences are including sessions on epigenetics, said Arthur Beaudet, a geneticist at Baylor College of Medicine in Houston.

"I think there's beginning to be a growing awareness that this is something that maybe people should start looking at," he said. "There may be a lot going on in human biology that we really haven't scratched the surface of."