Mapping the genetic “cascade”
By HEATHER HEILMAN

There’s a picture on the door to YiPing Chen’s office that depicts a yellow duckling with long fangs protruding from its bill. “Count Duckula” reads the caption. It’s a joke about Chen’s work.

No, he’s not creating duck vampires in the lab, but he has been able to grow tooth buds—the beginnings of teeth—in chicks. Why, you might wonder, would you want to do that?

“We’re interested in the genes that control organ formation,” explained Chen, an assistant professor of cell and molecular biology.

About 25 genes have been found to be involved in the development of teeth in mice. Almost all of them also are expressed in chicks. Chen speculated that by reactivating in the jaw region of the chicks one of the missing genes, called BMP4, a growth factor, as well as Msx-1, a transcriptional factor, tooth buds would develop. And he was right.

One of the eventual practical implications of this work might be the ability to reinitiate tooth development in people who have lost their teeth.

“I’ve always believed human beings have the ability to regenerate teeth, if you reactivate the genes at the top of the genetic cascade,” Chen said, noting that humans already develop two sets of teeth during their lifetime.

The main purpose of Chen’s work is to map out the genetic cascade, or progression, involved in the development of particular organs. Organs develop in the womb through a complex process of genes signaling other genes. Once scientists understand these processes, they can intervene in them.

“We’re trying to understand which gene is sitting at the top of the cascade,” Chen said. “If, in the future, we can identify the genes that are involved in this process, we can reinitiate or reactivate the genes on top.”

Humans and animals develop an incredibly diverse array of organs—from the heart to fingers to teeth—but the same set of genes shows up over and over again in the development of different organs in different species.

One gene, whimsically named “sonic hedgehog,” affects the development of a pinky at one end of your hand and a thumb at the other, as well as the development of molars in the back of your mouth, incisors in the front and canines in the corners. And BMP4 and Msx-1, the same factors involved in tooth formation, also are involved in the development of the palate, which separates the nasal cavity from the oral cavity. Mutations in the Msx-1 gene are associated with cleft palate, which occurs in one out of 600 human newborns in the United States. In research on cleft palates in mice, Chen found that if BMP4 is artificially expressed in mice embryos with mutant Msx-1, the cleft palate can be fixed and a normal palate will develop.

In this case, the cure for the cleft palate is not to reactivate the gene at the top of the cascade, but rather to bypass the defective gene and rescue the process further downstream. Eventually, this problem may be corrected in the human embryo as it develops.

Chen also is studying the genetic process that causes the heart to locate to the left side of the body. About one in 8,000 people are born with their heart on the right side, a condition called situs inversus. In some cases this is benign, but in others there are serious consequences.

“The heart is the first functional organ to develop,” Chen said. “It forms first as a straight tube, then loops to the right side, which results in the heart position in the left side of the body.”

Chen and his research team believe they have identified one of the genes that controls heart looping. The heart loops to the side on which this gene is not expressed. Eventually, the studies may provide insight for the prevention and treatment of laterality defects in humans.

Chen first became interested in muscle and cartilage development when studying embryology in China. He came to the United States in 1989 to study how the body’s anterior-posterior axis develops. He did postdoctoral work at Harvard, where he had the idea to induce the growth of teeth in birds. That project attracted the attention of the New York Times, which ran an article on the research last August.

Chen arrived at Tulane in 1997. He was lured here by the opportunity to work with department chair Ken Muneoka and by the promise of lab space in the new Israel building. He got his new lab as promised, where he continues the work of teasing out the subtle nuances of complex genetic processes.

Inside Tulane
February 1, 2001