Making Faces
A new team brings researchers and surgeons together to explore the origins of facial deformities
Our faces are windows to who we are – we use them to engage with others, we anguish over them as teenagers. A face can cause us to fall in love, make us smile or strike fear in our hearts.
And when a face does not develop as it should, it can shatter a life. A new team brings researchers and surgeons together to explore the origins of facial deformities Our faces are windows to who we are – we use them to engage with others, we anguish over them as teenagers. A face can cause us to fall in love, make us smile or strike fear in our hearts.
And when a face does not develop as it should, it can shatter a life. Doctors in the Division of Plastic Surgery at Cincinnati Children’s perform as many as 800 surgeries a year to repair craniofacial deformities. Most of those surgeries are to repair deformities that happen during fetal development.
Now, the medical center has recruited a research team to study what goes wrong during development to cause facial deformities. The researchers hold dual appointments in our Divisions of Developmental Biology and Plastic and Reconstructive Surgery.
Lead researcher on this new team is Rulang Jiang, PhD. Jiang comes to Cincinnati Children’s from the University of Rochester School of Medicine and Dentistry, where he has focused his career on understanding what happens in early development to cause cleft lip and cleft palate. He has discovered a career’s worth of complexity in just this one area.
“When you look at an intact baby face versus a baby with a cleft lip, how do you imagine what might have occurred during embryogenesis?” he asks.
Five not-so-easy pieces
The midfacial region that surrounds the oral cavity actually develops from five separate parts, Jiang says. “Not only are the facial prominences growing and merging at the same time, they are doing so as the cranium and the brain are expanding. So children with cleft lip, even though the phenotype may be similar from one child to another, the underlying causes could be dramatically different because so many regions of this craniofacial complex could be affected.” Jiang is particularly interested in the neural crest cell, a multipotent cellular nomad that arises from the early spine and travels throughout the body, setting up camp everywhere from the head to the heart to the gut. Neural crest cells play a major role in forming all the facial structures, including bones, cartilage, teeth, nerves and connective tissue.
As the neural crest cells begin to give shape to those five facial parts, what Jiang describes as “highly regulated, finely tuned cross-talk” across a complex network of molecular pathways directs the cells to migrate and proliferate on cue to form the framework of the face.
When that cross talk is disrupted or misunderstood, cells can overgrow, get off track and fail to form the structures properly.
Chris Runyan, MD, PhD, in his third of a six-year residency in craniofacial plastic surgery, sees daily — and is learning to repair — the damage that results from these missed signals. Although surgeons can restore facial structure and function with good cosmetic results, he says, it is not an easy road for kids.
“In these young patients, the face is growing so it’s difficult to get a fix with just one shot,” Runyan says. “The average kid with cleft lip and palate has six surgeries in a lifetime.
Many have many more than that.”
Models for study
Jiang uses mouse models to study the complexity of the signaling network and how things go wrong. In the embryonic stages — when most of the facial framework develops — the cellular and molecular processes involved are remarkably similar in humans and mice.
“More than 98 percent of the genes in humans have counterparts in mice,” says Jiang. “So what we learn using mouse models can often be directly applied to understanding the genetic basis in humans.”
Over more than a decade of studying these models, he has learned a great deal – including that there is still much to learn.
“We already know a lot about the genetic pathways at this point. What we need to understand more about is, what might be disrupted at each step in the molecular and cellular processes? What are the relationships between the molecules and pathways? And at the cellular level, how do they come together to control proliferation or migration of the cells?”
Cellular behavior is one area of focus for Samantha Brugmann, PhD. Brugmann is part of the newly formed craniofacial research team. She, too, has a dual appointment in plastic surgery and developmental biology.
Brugmann studies how the skeletal structure in the midline of the face forms – the portion that gives rise to the forehead, bridge of the nose and the philtrum, that small indentation just above the upper lip.
With the help of a three-year, $747,000 grant from the National Institute of Dental and Craniofacial Research, she is using an avian model to explore how defects in the cilia of neural crest cells might lead to facial deformities.
Cellular GPS
Brugmann believes that cilia on neural crest cells act as antennae, picking up molecular signals that direct their travels and tell them what to do. If those antennae are missing or defective, they can lose their way or continue to divide when they should be differentiating into skeletal elements.
“We’re using these models to look at how neural crest cells behave when they don’t have cilia. Can they start in a very dorsal location and migrate all the way into the mandible, maxilla and frontonasal area – or is their migration affected by not having cilia?”
She suspects that their migration might be affected by missing cilia; the embryos of chicks without cilia show signs of facial deformities. Brugmann attributes this in part to their inability to pick up signals from the hedgehog molecular pathway, which is crucial to proper development.
“When the cilia were defective, the neural crest cells couldn’t receive signals properly to tell them what to do and how to develop into the facial skeleton,” she says. “They were able to form skeletal elements, but they either were not in the right place, or they were duplicated. So the face started to get very, very wide.”
Her research will explore the role of the cilia in picking up these crucial signals by testing cells with cilia — and without.
“We’ll do migration assays to see if we put neural crest cells with cilia here, and we put the hedgehog signal over there, will the cells migrate towards the signal? And if they don’t have cilia, will they start searching around and not have directed migration anymore?”
Cilia’s growing role
Appreciating cilia’s role in early development is a departure from earlier thinking that they were merely vestigial organelles, Brugmann says. New genetic studies have proven their importance, and ciliopathies – diseases caused by defective cilia – are a new and growing area of research.
“There’s been a lot of interest in studying cilia, especially when people started to realize a lot of receptors are preferentially located there and that major developmental signaling pathways are affected when there’s a defect in cilia.”
While there is much basic science still to be understood about facial deformities, Jiang and Brugmann are eager to work in collaboration with clinicians.
“There are always important issues in basic biology that we need to understand. But working with the craniofacial surgeons, we can learn about clinical applications that basic scientists don’t often think about,” Jiang says.
Likewise, the surgeons hope to gain more insight into the problems they encounter.
“As surgeons, we can treat the problems, but we don’t have an explanation of how they develop,” says Runyan. “Better understanding could help us provide better treatment. It’s exciting to have basic scientists to work with on this.”
