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Study of epigenetics seeks to control genes' functions

By Eric Adler, Kansas City Star

15 September 2007: At 56, Hazel Soap of Louisburg, Kan., was ready "for God to take me home."

She had been diagnosed with a killer: acute myelogenous leukemia. She had six months to live, maybe a year.

Chemotherapy took her hair.

She vomited.

She prayed. "I'm ready."

Then her doctor, hematologist Barry Skikne at the University of Kansas Hospital, offered a last resort. A new drug. Experimental. Not radiation and not traditional chemo.

Instead, it was a drug based on epigenetics, a once obscure science now being studied worldwide, including in Kansas and Missouri, and whose implications are quickly turning the medical world on its Darwinian ear.

In short, it says this:

Much of who we are - from our eye color and IQs to many of the diseases we get - is determined by our genetic codes.

But that code, epigenetics holds, is controlled by a "second code" - by an array of tiny carbon and hydrogen molecules known as methyl groups that sit like off-switches along the surface of our genes ("epi" means "on top of").

Many of these methyl groups are there naturally. Others can be introduced. Some help us by turning off genes that aren't needed at the moment or might otherwise go haywire. Others, however, can short-circuit genes that protect us.

They can be added or removed by what we eat, drink and smoke, by the chemicals around us, perhaps even by how we were parented. Those life-altering epigenetic changes may be passed on from generation to generation.

In other words, say epigeneticists, theoretically the reason you get cancer today may have less to do with something you ate than what your grandmother ate and changed the work of her genes. That change got passed on to you. Likewise, the environmental stuff you're exposed to now may cause epigenetic changes that, for good or bad, could affect your yet-to-be-conceived children and grandchildren.

"A lot of people will find it scary, this concept that something that might have happened to their great-great-grandparent might be affecting their health today; and what happens to you might end up impacting your great-grandchild down the road," said epigenetic researcher Charles Caldwell, director of the Ellis Fischel Cancer Center at the University of Missouri. "But it's also very exciting."

Exciting, researchers say, because if our environment can turn genes on and off, maybe we can, too.

At KU, Hazel Soap steeled herself for five months of injections - one injection a day for one week out of every month.

If the drug was to work, it would do so by seeping into her bone marrow and epigenetically switching on a protective gene that would slow or halt her cancer's growth.

Her first shot came in October 2003.

"I'm doing exceptionally well," Soap said recently, her voice strong and sharp. "I'm heading into my fifth year of remission."

Worldwide, interest in epigenetics is booming.

In May, the National Institutes of Health listed epigenetics as one of its top five research priorities for the next five years.

In Europe, private and public laboratories are now engaged in the European Human Epigenome Project, to map the array of controlling surface molecules embedded in human genome.

At least a dozen pharmaceutical companies are hunting for new epigenetic drugs to treat everything from cancers to sickle cell anemia to schizophrenia to Alzheimer's disease. (In 2004, the Colorado-based Pharmion Corp., which has offices in Overland Park, received fast-track approval for Vidaza azacitidine, the drug used to treat Hazel Soap. Other drugs are in development.)

At the University of Missouri, Caldwell and colleagues are working under a $400,000 grant from the NIH to explore the epigenetic roots of lymphomas.

"Literally every cancer has epigenetic alterations," Caldwell said.

At laboratories worldwide, virtually every cancer - from breast to brain, liver to leukemia - is being explored in a new epigenetic light.

"We have a trial about to start in renal cancers and melanoma," said Jean Pierre Issa, a leading researcher at M.D. Anderson Cancer Center in Houston. "Other doctors are doing trials on ovarian cancer and lung cancer and so on."

The implications go far beyond cancer.

"People are studying epigenetics in just about every kind of human disease you can think of," Caldwell said.

That includes the main diseases of aging: diabetes, heart disease, dementias.

"If the tip of the iceberg is the human genome, this is the base of the iceberg," said Duke University researcher Randy Jirtle, a leader in the field that examines how environmental chemicals and nutrition might be affecting the epigenetic fate of subsequent generations.

In August, Jirtle and his team published research in the journal PNAS, the Proceedings of the National Academy of Sciences focusing on bisphenol-A, a common chemical in polycarbonate plastic.

"It's everywhere," Jirtle said. "It's in most hard plastics, clear plastics, like the containers your water comes in. It's used inside food cans. It's in dental sealants, adhesives - everywhere."

The chemical is already known to cause epigenetic changes. In his work, Jirtle exposed female mice to the chemical and later bred them. The mothers seemed unaffected, but their pups all later became obese, had fertility problems and either prostate or breast cancer.

In the main part of his experiment, Jirtle then fed the mothers folic acid or genistein, a compound found in soy. Both are nutrients also known to cause epigenetic changes, but opposite of those of bisphenol-A.

The question was whether feeding the mom the dietary supplements would save her next set of pups from a bad genetic fate.

It did.

"By giving the mom that diet, you're not curing her, but you're curing her offspring," said researcher Cheryl Rosenfeld, who is conducting similar research at the University of Missouri.

What makes epigenetics so significant, said Rosenfeld and others, is the dramatic way in which it is now bridging the chasm between nature and nurture, between what's caused by biology and what's caused by experience. In epigenetics, experience changes biology.

At the University of Ottawa in Canada, scientists are looking at the high rate of schizophrenia among Latin immigrants. One hypothesis is that the decreased sunlight (and thus vitamin D), together with stress and changes in diet, may be causing epigenetic changes which, in turn, have led to a rate of schizophrenia that is three times higher than average.

At McGill University in Montreal, scientists Moshe Szyf and Michael Meaney made epigenetic history in 2006 when they looked at the nurturing behavior of female mice. To no one's surprise, they found that baby mice that were lovingly groomed by their mothers turned out to be calmer and friendlier than mice that were not groomed. Good mothers produced good babies. Neglectful mothers produced bad babies. The surprise: The grooming produced calming brain chemicals that caused epigenetic changes. Those changes were passed on. The good baby mice gave birth to more good baby mice.

At Indiana University, researchers are investigating whether Alzheimer's disease may be the result of epigenetic changes spurred by diet, hormones or chemical exposure.

"This is what epigenetics is all about. I think this is why we're getting all these diseases," Rosenfeld said. "Your diet, your environment: You not only have to think about your epigenes, but your kids' epigenes."

But epigenetics still is in its infancy. Right now, at least, there's not much people can do to control their own epigenes, scientists said.

Drugs exist that can add methyl groups to our epigenes (to turn genes off) or strip them from it (to turn genes on). Newer drugs focusing on different areas along the epigenome are also being developed.

But these drugs all act broadly - turning genes on or off indiscriminately with the chance for considerable side effects. The drugs don't work for everyone.

As for diet: The list of chemicals or foods or nutrients that might be turning genes on or off is vast.

"The more we learn, the more we realize we don't know," said Caldwell, of MU.

Still, Hazel Soap of Louisburg knows this: She's grateful.

"I do get teary sometimes," she said. "I think it's the fact that I'm still here. I didn't expect to be."

What is epigenetics?

Epigenetic theory holds that a type of "second genetic code" exists on top of our DNA. Scientists think that environmental factors - from our diets to the chemicals we're exposed to, perhaps even our parenting - can affect our genetic fate by turning genes on and off. In addition, they think those "epigenetic" changes can be passed on to future generations.

To reach Eric Adler, call 816-234-4431 or send e-mail to eadler@kcstar.com.