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NEWS FROM THE FORSYTH INSTITUTE 140 The Fenway, Boston, MA 02115 · 617-262-5200 · www.forsyth.org
FORSYTH AND HARVARD MEDICAL RESEARCHERS FIND KEYS TO LEFT/RIGHT ASYMMETRY Boston, Oct. 4, 2002------Researchers at The Forsyth Institute and Harvard Medical School have discovered a novel molecular mechanism that determines right/left asymmetry—that is, for example, whether the heart is on the right or left side of the body—in vertebrates. They have also located the genetic material that encodes for the mechanism and have determined that the process through which a fertilized egg begins left-right patterning begins much earlier than was previously believed. The findings, to be published in the October 4 issue of Cell, have important ramifications for understanding human conditions such as right-left hand preference, mirror image twins, right versus left brain dominance, and birth defects that cause organs to develop on the wrong side of the body, according to first author Michael Levin, PhD, an Assistant Member of the Staff at Forsyth. "We are only now beginning to address the mysterious evolutionary and developmental origin of asymmetry—the very first step which allows the embryo to reliably know its left from its right," Levin said. "Orienting the left-right axis is crucial for later stages of development since it controls not only the shaping of the asymmetric visceral organs (stomach, liver, gall-bladder, spleen, heart), but also of the brain."The findings, key to understanding what controls the shaping of tissue, may also have future implications for the treatment of cancer (which can be viewed as a condition in which cells have lost the ability to assume their proper position) and for organ re-growth. " We now have a new handle on molecular mechanisms by which natural electric fields are set up and serve to control cell behavior and tissue shape," Levin said. We believe that this knowledge will, one day, increase our ability to control cell function in biomedical contexts such as tumor growth control and limb regeneration."Working with frog and chick eggs, the researchers determined that an ion pump sets up gradients of K+ and H+ ions which are asymmetric across the midline, and that these gradients are required for correct L/R asymmetry. The researchers also found an asymmetric localization of mRNA for this pump at the 4-cell stage, which shows for the first time that asymmetry is assigned far earlier than was previously believed—within two hours of fertilization. Asymmetric function of the ion pump regulates cascades of gene expression that in turn provide cues to the developing organs, instructing their asymmetric development. "This is extraordinarily important because it provides the earliest known mechanism for determining left-right asymmetry," said senior author Mark Mercola, PhD, professor in the stem cell and regeneration program at the Burnham Institute. It was in his prior laboratory at Harvard that much of the work was carried out while Levin was a fellow there. "The mechanism of an electrical current being involved in early patterning is an extremely novel idea that opens up new avenues of research." "For years, scientists have been thinking about the importance of the many electric fields which are set up by cells and tissues," explained Mercola, who left Harvard this summer. "This finding shows specific function for the establishment of a body’s axis—a function that has never been considered before." Clifford Tabin, PhD, professor of Genetics at Harvard Medical School, called the study: "a major breakthrough, tracing the origin of left-right organization to the very first stages of embryonic development and implicating a regulatory mechanism heretofore unrecognized for its significance in this context: the control of ions moving across cell membranes by the so-called H+/K+-ATPase." Every year in the US approximately one in 8000 babies is born with laterality defects in which internal organs are misplaced, leading to serious deficits in function. The current research sheds light on a new genetic and environmental cause of these conditions. First author Michael Levin, PhD, is Assistant Member of the Staff at The Forsyth Institute. Levin is also an assistant professor at the Harvard School of Dental Medicine. The current project was initiated in the Harvard Medical School laboratory of corresponding author Mark Mercola, PhD, now a professor at the Burnham Institute in La Jolla, California.* The Forsyth Institute is an independent, nonprofit research organization focused on oral, craniofacial and related biomedical sciences.
For copies of the article, contact Cell Press at 617-397-2825 or press@cell.com.
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