G is for Genes and Faces

Have you ever thought about what truly constitutes a face? Jill Helms, director of the cellular and microbiology lab in the department of orthopaedic surgery, thinks about it every day - and not in any superficial way.

For this peridontologist with a PhD in neurosciences, who also carries a joint academic appointment in the Schools of Dentistry and Medicine, a face is not just the sum total of its surface features. It is instead a culmination point of multiple genetic processes that create and maneuver bone and skin into place. Put another way, faces are structures upon which genes also shape identity. Yet something so distinctly ours begins distinctly like everyone else's — a fact that is true of other animals as well.

"In the early developmental stages, the primordia that ultimately give rise to an elephant's trunk, a toucan's beak or a human face are indistinguishable from each other. It's exciting to think about the genes that have to turn on and turn off to make all these diverse facial forms."

It is also instructive, one reason why Helms' research into the genetic controls and protein interactions underlying the growth and development of bone and cartilage has made her an expert in why things go wrong. "The number of craniofacial birth defects in the US is large and sometimes life-altering in a very negative way, particularly as children with defects become more self-aware," says Helms. "Evolution has made the face important. It's something we as humans pay attention to, so even slight defects in facial patterning or symmetry are noticed by others."

Animal models are key to Helms' work, which so far has singled out proteins called sonic hedgehog (named after a video-game character), fibroblast growth factor and bone morphogenetic proteins, as well as vitamin A (retinoic acid) as essential players in organizing bone and tissue into a completed face. Identifying their successful interplay requires that Helms and her colleagues literally get under the skin and manipulate developmental signals within and among cells. The goal is to track cause and consequence in her preferred model system — bird embryos — and to alter facial form.

Sonic hedgehog, for example, is known to direct aspects of limb growth and lung development, just as vitamin A — in small doses — helps "stitch" a face together. The balance between them is delicate. Too much vitamin A during pregnancy results in a high rate of head and facial defects.

In the worst cases, fetuses develop a condition known as holoprosencephaly, in which the middle section of the face is missing and the remaining features are compressed. Helms and her laboratory colleagues determined the cause five years ago; high doses of vitamin A during fetal development suppress sonic hedgehog activity. Yet, using chick embryos, Helms has also determined that too little of the same vitamin during fetal development results in a near-identical condition — and that doses of sonic hedgehog and fibroblast growth factor, given after blocking vitamin A, restored normal development.

"Finding what causes the differences and defects in animals is a good indicator of what controls the same pathways in humans," says Helms. In one experiment, conducted by a postdoc in her lab — again using only bird embryos that were otherwise not viable — the researchers were able to switch tissues between a duck and a quail and successfully demonstrate that the targeted tissue did indeed control facial formation.

"The duck embryo developed a quail's beak and the quail began to produce a duck's beak," explains Helms. Similar insights into the precise recipe of proteins behind normal human facial formation may one day allow for fetal interventions to prevent the birth of children with cleft lip and palate and other more serious head and brain defects. Fetal imaging already has progressed to the point that even tiny defects can be spotted early, Helms explains. Fetal cells circulating in the mother's blood, although very few in number, can now also be isolated and amplified — allowing for genetic mutation tests and clarity about the type of defect taking shape.

"I am very focused on what we can do to help patients, but I admit, it is also fun opening up this window on evolution."

by Jeff Miller