[Pharmwaste] Study of epigenetics seeks to control genes' functions

[DeBiasi,Deborah]

http://www.kansascity.com/105/story/277128.html


Posted on Sat, Sep. 15, 2007 
Study of epigenetics seeks to control genes' functions
By ERIC ADLER
The Kansas City Star 
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."



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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 at kcstar.com.

Deborah L. DeBiasi
Email:   dldebiasi at deq.virginia.gov
WEB site address:  www.deq.virginia.gov
Virginia Department of Environmental Quality
Office of Water Permit Programs
Industrial Pretreatment/Toxics Management Program
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