Nailing Down the Window
Research Fellow Pinpoints Exact Time When Cleft Palate Occurs in Womb

BY RUTH SCHECHTER

WINTER 2007 -- For thousands of babies born wih a cleft palate, early life can involve multiple surgeries, followed by specialized care and therapy. But what if it were possible to repair the cleft before birth? Or better yet, prevent the damage altogether? 

That challenge got postdoctoral fellow Karen Liu, PhD, thinking. Straight out of graduate school, and putting in the laboratory hours required to qualify for a career in research, Liu wanted to combine her interests in molecular biology, embryonic development, and basic science. Using specially designed mouse models, she and her team used a technique called chemical genetics to explore the exact window of time when cleft palates and sternum clefts occur, allowing the scientists to potentially modify the condition in the unborn fetus.

A Big First Step

''It's possible that someone in the next building has a new way of doing things that will completely change the way you approach your project. A program like Regenerative Medicine is great because it forces cross-disciplinary interactions and allows you to work with a wide range of people.'' -Karen Liu, PhD

The results of Liu’s investigation-- though still too early to apply to humans--show great promise in terms of understanding how and when clefts form in the womb and for the possibility of preventing conditions in unborn patients rather than trying to treat them after birth.

''It’s an important first step in the development of fetal therapies,'' says Michael Longaker, MD, director of the Children’s Surgical Research Program and the Deane P. and Louise Mitchell Professor in the School of Medicine. ''Our hope is that this basic advance eventually will make a significant difference for children with clefts and other birth defects.'' 

The research creates new insights into how palates are formed and fuse, which in turn may lead to better understanding of what goes wrong in congenital disorders. Cleft palates are one of the most common birth defects in the world, affecting about one in every 2,000 births.

A Two-Day Timeframe

Liu took advantage of a strategy to disrupt the function of GSK-3beta, a protein that plays an important role in biological development. Mice that had been genetically engineered to make GSK-3beta unstable developed cleft palates. Liu found she could reverse the defect by injecting the pregnant mother with a drug called rapamycin, which returned the protein’s function to normal. She also determined that she needed to normalize the protein during a very specific timeframe: In these mice, cleft palate is the result of growth imperfections that occur in a two-day window during embryo development, while sternum development takes place--with normal protein function--two days later. 

''The beauty of the technique is that it nails down the developmental window for a specific embryonic event,'' Longaker says. ''We don’t need to treat the mother long term, but just during the time that the organ or structure is forming.''

Fellows Play Key Role

Liu, who now has her own laboratory at Kings College London, was one of the more than 1,000 postdoctoral fellows working in basic science and clinical research laboratories throughout Stanford. Fellows play a critical role in moving science forward, and they are encouraged to think in terms of translational medicine--the integration of scientific studies to the diagnosis and treatment of disease--that has the most potential for improving children’s health. 

Liu was prompted to ''think outside the box'' and to take a collaborative approach to solving her research questions, which led to close interactions with mathematicians, chemists, and neurobiologists. She then was able to blend her interests in developmental biology with Longaker’s expertise in craniofacial surgery and stem cell biology, benefiting from the insights of experts who normally might not work together.

''I wanted to pick up some new 'tools' for my developmental studies, so I guess I was already thinking in a multidisciplinary direction,'' says Liu. ''This project required coordination of a diverse group of people--and their skills. I think it is important to talk to a variety of people about your project. It’s possible that someone in the next building has a new way of doing things that will completely change the way you approach your project. A program like Regenerative Medicine is great because it forces cross-disciplinary interactions and allows you to work with a wide range of people.''

How Research Helps

Several key advances are required before Liu’s research can have clinical relevance, but the results demonstrate that chemical genetics strategies can prevent a birth defect in mice--an important breakthrough concept. Her work sheds light on a vital part of the intricate process of fetal development, and moves science one step closer to the possibility of new therapies.''

''It is quite amazing that a single fertilized egg can develop to become this incredibly complex creature,'' she says. ''The process is so complicated and there is so much that is unknown. It’s important for us to 'translate' basic science and explain the medical impact of this work. I think it’s reasonable for the public to ask, 'What good is this research? How does it help people?' And we should be able to explain.''