Teeth Earn Starring Role in Field of Regenerative Medicine

By Jeffrey Norris

By the time kids begin school most have learned that if they lose any of their new “permanent” teeth, those teeth will be lost forever. But did you know that some mammals -- mice, for instance -- have teeth that grow continuously? In Greek mythology, sowing the teeth of a fierce dragon caused fully armed warriors to spring forth and fight. Today it’s no myth to say that studies of the much meeker mouse might guide researchers to a more constructive harvest that benefits humans. Lessons learned about where, when and how teeth grow throughout life in mice may lead to strategies for re-growing teeth and treating or preventing human developmental anomalies that impact the face and dentition. These craniofacial anomalies, the best known of which are cleft lip and palate, are among the most common of all birth defects.

Teeth recently have earned a starring role in the field of regenerative medicine, and at UCSF, Ophir Klein, MD, PhD, is a leading light. His lab is a beacon for promising postdoctoral fellows who want to explore how stem cells generate new teeth and how development goes awry in craniofacial disorders. Klein, who received a New Innovator Award from National Institutes of Health Director Francis S. Collins, MD, PhD, in September, also is funded by a major grant from the California Institute for Regenerative Medicine. This $3 million state grant funds a research proposal titled “Laying the Groundwork for Building a Tooth: Analysis of Dental Epithelial Stem Cells.”

A Proving Ground for Regenerative Medicine

Humans and animals possess very small, self-renewing populations of stem cells. These vary in potential and potency, depending on developmental stage. At one extreme are embryonic stem cells, obtainable just a few cell divisions after sperm fertilizes egg. These cells can give rise to virtually any cell type in the body. Other stem cells are organ or tissue specific. Stem cells are rare. The vast majority of human cells are specialized and mature and they have no stem cell capabilities whatsoever. “We don’t know if these particular stem cells in mice also exist in humans,” Klein says. “There are reasons to think that some of them might. But what we really want to understand are the mechanisms by which stem cells can contribute to dental renewal.”

In August 2009, Klein became the director of the Craniofacial and Mesenchymal Biology (CMB) Program at UCSF. “CMB is a relatively new program that we are trying to build,” Klein says. “Our goal is to have a translational program that spans basic research similar to my own, and that extends to clinical work.”

“Probably half of the basic research people in my lab are focused on trying to understand the genes and cellular behaviors that underlie the continuous growth of the incisor in the mouse. The rest investigate the role of different growth-factor signaling pathways in the development of structures within the embryo.”

Klein wants to use stem cells to grow new teeth. He views teeth as a convenient starting point and proving ground for all of regenerative medicine. Teeth and the oral cavity are very accessible in comparison to the large, vital organs, yet what Klein learns about teeth is bound to apply to growing these other tissues. “There are a lot of sophisticated aspects of tooth function,” he says, “but you might not have to form a tooth as perfectly as a heart or kidney in order for it to function adequately.” Still, growing teeth is an ambitious project. Klein is optimistic about success, but it will require many years to achieve, he says.

Late Bloomer Becomes Medical Geneticist

Given his credentials and relatively young age, it’s odd to hear Klein describe himself as a late bloomer. But the San Francisco Bay Area native initially shunned the career path advocated by his father, who was trained as a scientist. However, even though Klein earned his degree at UC Berkeley in Spanish, an introductory chemistry course led to an interest in biochemistry and eventually to a job in the lab of Daniel Koshland Jr., PhD, a professor and luminary in the field. That experience in turn led Klein to Yale, where he completed a combined MD/PhD program and then a residency in pediatrics. He came to UCSF for a postdoctoral fellowship with developmental biologist Gail Martin, PhD, and for training in medical genetics, and before long was viewed as a promising faculty candidate.

Today, Klein is an assistant professor of orofacial sciences and pediatrics, with a primary appointment in the UCSF School of Dentistry and a secondary appointment with the UCSF School of Medicine. He also is a core member of the Institute for Human Genetics, a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and a member of the Helen Diller Family Comprehensive Cancer Center. As a medical geneticist, much of Klein’s clinical practice is based at the UCSF Center for Craniofacial Anomalies, where he handles diagnostics, risk counseling and case management as part of a medical team that also includes plastic surgeons, orthodontists, pediatricians, pediatric dentists, pediatric neurosurgeons, dermatologists, otolaryngologists, speech pathologists, nurses and social workers. Many medical students, dental students, and doctors and dentists training for specialties spend time at the center, and Klein has an opportunity to share ideas with many colleagues and students.

“People in the clinic are fantastic at getting done what needs to be done, but they may not always have the inclination to think of ways to integrate basic science into clinical practice,” he says. “I think people who do research can add value to clinical medicine when they inject underlying ideas about biological mechanisms.” Klein leads clinical as well as basic research. “We are trying both to understand tooth and craniofacial malformations in a variety of syndromes, and also to look for the genes responsible for isolated tooth malformations in humans.”

Many patients’ parents are more than happy to have Klein and his research team learns more about the conditions affecting their young children. “If you happen to be a physician interested in craniofacial anomalies, and you’re lucky enough to be at a place that has both a great dental school and a great medical school, then it’s a perfect job,” Klein says. “I feel really happy to be a part of the School of Dentistry. I believe they really ‘get’ what I am interested in, and they have been really supportive.”