New published animal research suggests that one day it could be possible to prevent certain birth defects in offspring - cleft palate, for one - through treating mothers during pregnancy.
Of course, pregnant women always have been on the receiving end of a barrage of advice about which substances to ingest for the best health of their little cargo, such as the recommendation to get plenty of folacin to avoid spina bifida. (Other tidbits, such as one book's recommendation to limit "wicked" foods such as cupcakes to once a month during pregnancy, have been closer to hysterics than help.)
But according to research published Feb. 11 in the Nature early online publication, the difference between things like folacin and the new approach is that the findings mark one of the first, if not the first, demonstrations of using a small molecule to prevent a birth defect, senior author Michael Longaker told BioWorld Today,
Cleft palate is "one of the most common forms of birth defects, but it hasn't been easy to unravel," Longaker said. It is likely an interaction of several genes and environmental factors that go awry when cleft palate develops. Surgical approaches to closing the palate, while often successful, are very intensive. Multiple surgeries are required throughout the growth phase to correct a cleft lip or palate.
For the work reported in Nature, Longaker and his team at Stanford University School of Medicine used a combination of a destabilizing gene sequence and a small molecule to reversibly knock out a form of glycogen synthase kinase known as GSK-3 beta.
Though it previously had not been tied to palate formation, GSK-3 beta is a well-known player in development. In fact, previous studies had reported that GSK-3 beta knockouts do not survive until birth. Longaker said that there were many possible reasons for why his team's mice survived longer, though they too died perinatally.
The researchers used their reversible knockout technique to show that GSK-3 beta is important both for the formation of the palate and the proper development of the sternum, but at different times in fetal development. Reinstating GSK-3 beta activity with rapamycin between embryonic days 13.5 and 15 corrected the palate defect, while later reinstatement was necessary for normal development of the sternum.
For now, the findings remain in the realm of basic research. Longaker said that there is no "intuitively obvious" way to translate his findings into a prevention strategy for cleft lip and palate. Such a strategy would require: an ability to predict which fetuses are at risk for a birth defect; knowledge of an effective, small-molecule-based therapy that can prevent the defect; and an accurate method of assessing fetal age to allow time-appropriate administration of the therapy.
As basic research, however, the technique already allows new insights into the timing of fetal development. Longaker said that in his opinion, the main significance of the work lies in showing "how chemistry and chemical biology can be used to dissect out developmental windows."