WASHINGTON, DC -- In the early stages of fetal development, a nudge in the wrong direction can lead to irreparable birth defects, such as major brain and facial deformations. New research from the University of California, San Francisco shows that a brief deprivation of vitamin A in the heads of developing chickens can generate these severe craniofacial deformities, and that dosing the chicken embryo with a regulatory protein can restore a near normal face. The results suggest that, someday, carefully timed protein treatments in human fetuses might repair cleft palate and milder forms of some birth defects.
The research was presented here today (February 18) at the annual meeting of the American Association for the Advancement of Science, by Jill Helms, DDS, PhD, a UCSF professor in the department of orthopedic surgery.
If you're like most people, your face is reasonably symmetrical and everything is more or less in the right place. One series of developmental steps ensures this, and helps form many connections in your brain as well, said Helms. However, a dose of alcohol or carcinogens at the wrong time during development, or a genetic defect, can disturb this process and lead to birth defects such as holoprosencephaly, which affects 1 in 250 fetuses and 1 in 16,000 live births. Fetuses with this condition look as if someone had removed the middle section of the face and compressed the remaining features together.
While pediatric surgeons can repair cleft lip and palate, and fetal surgeons are studying the possibility of repairing more serious defects in the womb, Helms and other biologists are studying a molecular approach to the problem. "The goal is to develop a strategy for treatment of craniofacial defects in utero, or ultimately to prevent these defects in the first place," she said.
To develop such treatments, researchers must first understand the web of different proteins that interact and influence correct face and brain development. Researchers have learned that one central player is the sonic hedgehog protein, which is named after a video game character, and which directs aspects of limb growth and lung development.
Vitamin A, or retinoic acid, is also important -- excess doses during pregnancy, such as from the prescription acne medicine Acutane, can lead to very high incidence of holoprosencephaly and other head and facial defects. Helms and her colleagues discovered a few years ago that these excessive doses of vitamin A suppress sonic hedgehog activity in the embryonic facial tissue.
Since at least some dietary vitamin A is essential for normal fetal development, Helms and her colleagues wanted to study the effects of a vitamin A deficit. They treated developing chicken embryos with a molecule that blocked the vitamin A receptor. After trying several different durations and timings of this treatment, Helms' group found that even a few hours of vitamin A blockage at the right stage of development led to severe holoprosencephaly. "We produced chick embryos that completely lacked a forebrain, and had no middle and upper face. Such conditions are lethal both in humans, and in these chick experiments," she said.
In an attempt to counteract these defects, the researchers dosed the embryos shortly after the inhibition of vitamin A with various proteins involved in regulating face and brain development. They found that strategic doses of sonic hedgehog and another protein called FGF2, restored normal development of the chicks' faces and brains.
"Obviously this is long way from treating a human fetus but it's a very important first step," Helms said.
Before such prenatal treatments are developed, study of these developmental molecules may help doctors to give very early diagnosis of developmental problems, by spotting a critical mutation or low production level of a key protein, Helms said. "We will be able to help parents understand whether the fetus has any life-threatening malformations, and whether they want to terminate a pregnancy if they would have a child with a very severe defect," she said.