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Triggering the switch

Triggering the switch
Researchers study how the environment affects genes in the womb

May 2012

by By Sheila Hotchkin

"The genome era is over. We are now in the epigenome era, when it will be important to consider gene-environment interactions - not the gene alone - as the basis of health."

So says Peter Nathanielsz, M.D., Ph.D., who knows well The Eagle pub in Cambridge, England, where the genome era began. There, on Feb. 28, 1953, Francis Crick strode in at lunchtime, declaring that he and James Watson had "found the secret of life." They had identified DNA’s double-helix structure.

That was followed by efforts to understand how DNA is encoded and sequence entire genetic codes - or genomes - of living creatures. By 2003, the 50th anniversary of Watson and Crick’s discovery, the full human genome was sequenced.

"Conceptually, we’ve passed the genome era," Dr. Nathanielsz declares. "We are now in the post-genome era, when we need to understand how the environment modifies - switches on and off - genes."

The new frontier, called epigenetics, is the study of lasting change in how genes are expressed without alteration to DNA’s underlying sequence. In many cases, these new traits can be passed to future generations. Although the term was coined in 1942, epigenetics has attracted intense scientific interest only in the last decade.

Dr. Nathanielsz and his collaborators at the Center for Pregnancy and Newborn Research, in the Department of Obstetrics and Gynecology in the School of Medicine of the UT Health Science Center, are well positioned to contribute to this emerging field.

For decades, they have studied how conditions in the womb and immediately after birth impact health and susceptibility to disease throughout life and across successive generations. This is called "developmental programming" or "fetal origins of disease." Compelling evidence suggests these phenomena have an epigenetic basis.

"You are born with a deck of cards from your mother and father," Dr. Nathanielsz says, "then, from the moment the sperm hits the egg, that deck of cards is modified.
Environmental influences such as poor maternal nutrition instruct your genome, telling you that you can’t play the ace of spades - because it has been suppressed by environmental influences. That gene is just not going to work, or at least it’ll work much less. Another gene may be switched on too much. It is the gene-environment interactions that are fundamental."

Dr. Nathanielsz’s personal story intertwines with the emergence of epigenetics. He studied at Cambridge University, where Sir Joseph Barcroft realized decades earlier that a fetus is not merely a small adult but lives by a distinct set of rules. Cambridge, as a result, was the birthplace of fetal physiology, a precursor to developmental programming.

Immersed in this tradition, Dr. Nathanielsz earned his Ph.D. studying fetal sheep. He left Cambridge for the UCLA and then Cornell, where he met three members of the current team: Thomas McDonald, Ph.D.; Cun Li, M.D., Ph.D.; and Mark Nijland, Ph.D. No one grasped how significant such research would become. "We were just doing pure basic science," Dr. Nathanielsz said. "There’s a real lesson here. Pure basic science is incredibly important."

Then British physician David Barker showed that low birth rate raises heart disease risk - termed "the Barker hypothesis" by the British Medical Journal in 1995. The idea that challenges faced in the womb could have lifelong effects was greeted with skepticism but now has widespread acceptance.

Dr. Nathanielsz was at the forefront, authoring a book for general audiences, "Life in the Womb: The Origin of Health and Disease," in 1999. After a stint at New York University, he arrived in 2004 at the UT Health Science Center, where he led a team with a nearly unparalleled ability to study developmental programming across species: rats, sheep, non-human primates and, in translational research, humans.

At the Health Science Center, Dr. Nathanielsz works with Drs. McDonald, Li and Nijland, as well as Leslie Myatt, Ph.D.; Thomas B. Jansson, M.D., Ph.D.; Alina Maloyan, Ph.D.; and Theresa Powell, Ph.D. They collaborate with others, including Laura Cox, Ph.D., at the Southwest National Primate Research Center in San Antonio; Elena Zambrano, Ph.D., of the National Institute of Nutrition, Mexico; Matthias Schwab, M.D., Ph.D., of Friedrich Schiller University, Germany; and Stephen Ford, Ph.D., of the University of Wyoming.

This spring, Dr. Nathanielsz will receive the top honor of the leading organization in his field, the Society for Gynecologic Investigation. He stepped down as director of the Center for Pregnancy and Newborn Research on Jan. 1, handing the reins to Dr. Myatt, but has no intention of leaving research: "This is too important, and too exciting an area to leave."

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