Basic and Translational Research
Understanding Craniofacial Development
No region of our anatomy more powerfully conveys our moods and emotions than the face, nor elicits more profound reactions when a disease or genetic disorder leaves behind a disfigurement. In recent years, remarkable strides have been made toward elucidating the molecular mechanisms that regulate craniofacial morphology. Key to those insights is a deeper understanding of the cranial neural crest, an embryonic cell population with nearly unparalleled pluripotency. What factors drive cranial neural crest cell migration, proliferation and differentiation has been under intense investigation for nearly 150 years, yet we are still gaining insights into this regulation through the use of experimental and genetic manipulations in mice, birds, and fish.
The most basic features of the face go back to the dawn of vertebrate development and the master sculptor of the face is evolution. Following in the footsteps of Darwin (whose interest in beak morphology was piqued by studying domesticated pigeons), investigators continue to unravel how variations in facial form arise. These discoveries are not only applicable to the bird beaks: Nature appears to have developed a common blueprint for the face, the same molecular mechanisms that control growth and patterning in a bird beak also regulate facial development in mammals.
Beyond understanding the genetic, molecular, and cellular processes that regulate normal craniofacial development we must also remember how differences in facial anatomy deeply affect an individuals’ self-perception and their acceptance in our beauty-conscious society. Poets and scientists alike recognize that the face is an elemental part of our makeup. We must constantly remember how “looking different” can impact all aspects of a person's life, far beyond the physical limitations that may be imposed by a deformity.
Biomechanics and Implant Biology
Biomechanical conditions dictate how tissues heal. If sub-optimal mechanical boundary conditions prevail, then even the most potent stem cell-inducing factors and cell therapies are ineffective. Consequently, our laboratory has focused on the simple question of how skeletal stem cells, residing within a bone injury site, actually respond to mechanical stimuli. In this proposal our goal is to understand how skeletal stem cells that surround an implant respond to the mechanical stimulus of implant loading. We have, for the first time, the ability to precisely control and quantify the mechanical stimulus and then to directly test how that mechanical stimulus affects cell behavior.
In this proposal our goal is to understand how skeletal stem cells, residing within a bone injury site, actually respond to mechanical stimuli.
Using novel, genetically engineered mice we can detect the type of physical stimulus required to transcriptionally activate the Wnt signaling pathway; we can then follow cells that respond to this mechanically-induced Wnt signal and determine their ultimate fate in an in vivo environment.Never before have we had the ability to so precisely regulate the molecular signals and mechanical stimuli that shape the skeleton Our long-term goal is to leverage this knowledge, and our understanding of mechanically-coupled Wnt signaling, to optimize bone regeneration in a variety of contexts including implant osseointegration.
Aging and the skeleton
Our skeletons become progressively more fragile as we age and this fragility translates into poor bone healing potential. Why does this happen? And can the effects be reversed? Stem cells in the bone marrow cavity are partly responsible: instead of becoming bone-producers, these stem cells become fat-producers. Understanding when and how human stem cells degenerate may explain why some conditions, such as delayed bone healing, increase with age and also why bone grafts from elderly people tend to fail.
Our research focuses on mesenchymal stem cells (MSCs) that reside in the marrow cavity. We know that MSCs from healthy people over age 65 make less bone compared to MSCs from healthy people under age 35, irrespective of their sex. We set out to understand why MSCs lose this bone-forming capacity and have found that bone marrow from healthy, aged animals has significantly reduced levels of the stem cell factor, Wnt3a compared to bone marrow from healthy young animals. Treating bone marrow from aged animals with Wnt3a restores their bone-forming ability back to levels seen in bone marrow from young animals. We are working on moving these kinds of laboratory discoveries into clinical applications. As the 78 million-member baby boom generation enters their seventh and eighth decades of life they are living longer and expecting to enjoy better fitness and health than previous generations. We hope that these findings will translate into “regenerative medicine” strategies that have the potential to transform musculoskeletal health in the elderly.
Building a tooth
William Blake famously penned, “To see the world in a grain of sand and to see Heaven in a wildflower…” (W. Blake, 1803): which is an unlikely- but fitting- metaphor for the study of the dentition. By unraveling the tissue interactions that control the development and patterning of teeth, we are gaining new insights into how this unique craniofacial organ is generated. One day, soon, these same factors may be harnessed to regenerate a diseased dentition. For example, research in our group has focused on regenerating the dental pulp.
Our goal of regenerative dental medicine is to stimulate from stem/progenitor cells residing in the pulp cavity the generation of dentin and in doing so, preserve the vitality and function of teeth.
Most toothaches are the result of chronic bacterial infections that cause inflammation of the connective, vascular, lymphatic and nervous tissues occupying a chamber in the center of the tooth. When these tissues, collectively referred to as the pulp, become chronically inflamed they must be removed in a procedure known as a root canal treatment. In an effort to treat these conditions, a century’s old procedure called pulp capping is often employed. When the inflammatory insult is acute, and the extent of trauma is mild, then the pulp itself can sometimes mount a repair response. Our goal of regenerative dental medicine is to stimulate from stem/progenitor cells residing in the pulp cavity the generation of dentin and in doing so, preserve the vitality and function of teeth. We are testing whether WNT proteins can stimulate stem cells in the adult pulp, which would result in a superior repair repair response. Our data is encouraging: rodent pulp cavities treated with WNT show significantly more dentin formation, suggesting that a therapeutic strategy involving a WNT protein may one day obviate the need for root canals.
A Tour of Unkown Parts: An exploration of human developement, repair, and regeneration.
Continuing Studies, Winter 2011, 2013
Sometimes people see the body as a machine, a feat of engineering and adaptation. Others have described the body as a wonderland, whose inner workings are the source of continual amazement. Haven’t we all wondered a bit about the mysteries of our innards? In this course we will survey the function of a select group of organs, ranging from our largest (the skin) to our hardest (the skeleton); from our most delicate (the eye) to our most intimate (the face).We’ll discuss the functions of these organs, and explore the embryonic landscape from which they developed. We’ll also investigate how various organs respond when injury or disease strikes, and in doing so set the stage for understanding how advances in the new field of regenerative medicine have the potential to enhance the repair and stimulate the regeneration of some of these vital parts.
Thirty Two & Counting: The teeth we have and the ones we’d like to make.
Is it possible to build a tooth? This is a question that many of the top dental scientists currently are working to answer. In this course, we will survey the dental organ in search of clues and insights into what is required for making teeth. We’ll explore the anatomy of the dental organ, its function, and the embryonic mechanisms that shape and sharpen the teeth we are given from birth. We’ll also investigate how the dental organ responds to disease and acute injury. Collectively, we will use this to understand the possibilities that await in a new field of dental regenerative medicine and ask a new question: How do we build new teeth?
The Ultimate Face Book: understanding facial development, deformities, and differences.
We take for granted that faces have two eyes, a nose and a mouth. What happens when nature produces an animal with three or four eyes, two noses and two mouths? These anomalies and others stretch our imagination and provoke us to contemplate the instruction manual by which Nature assembles our faces.
This class is designed to explore the field of craniofacial biology. We’ll begin by studying the embryonic process of facial development and in doing so, we’ll lay the foundation for understanding birth defects that distort the appearance of the human face. Students will also have the opportunity to study some of the new methods being used to reconstruct the face when diseases or injuries traumatize this most important part of our anatomy. At the conclusion of the course, students interested in biology, medicine, genetics, and those with a sense of esthetics will understand how it is that "a man finds room in the few squares inches of the face for the traits of all his ancestors; for the expression of all his history, and his wants."
Hippocrates Challenge: Transforming science education through gaming
In this class, participants learn by doing. You and your classmates will combine your creative and analytical skills to assist design a massive open online course (MOOC) aimed at transforming the way people learn about the human body. This represents the first game developed at Stanford's School of Medicine designed to introduce students to the fields of medicine and biomedical research. We've developed a prototypical game, Hippocrates Challenge, which dares gamers to explore, collaborate, take risks, hypothesize, and problem-solve around a subject matter that is both complex and far-reaching- but which begins simply and with an engaging premise: namely, how good are you at playing doctor?
We will provide a starting point, the necessary medical expertise, and some short instructional lectures but together we’ll define the end product. Our ultimate goal is to collectively devise a way to help students- of all ages- experience medicine and science as an engaging process of mystery, discovery, and innovation.