Although about half of all birth defects involve the face and skull, scientists remain unclear about why most occur. To help families at risk for these conditions, what's needed is a comprehensive and systematic understanding of how the faces of healthy children develop and what goes awry to cause common malformations. With today's improved technologies, researchers can generate megabytes of information in a single experiment on hundreds of genes that are involved in the process. The challenge now is to learn how best to integrate this information into a meaningful whole, while adding new data to form a more comprehensive picture of this complex developmental process.
The integration process just got a lot easier. The National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health, announced today it has issued the first 11 research and technology grants of its new FaceBase Consortium. The five-year initiative will systematically compile the biological instructions to construct the middle region of the human face and precisely define the genetics underlying its common developmental disorders, such as cleft lip and palate. The mid-face includes the nose, upper lip, and the palate, or roof of the mouth.
As a key part of the initiative, a one-stop, encyclopedic database of head and skull, or craniofacial, development will be created and maintained to allow scientists to mine the riches of the information enabling them to more rapidly and effectively generate hypotheses and accelerate the pace of their research. The database, called FaceBase, will be free and publicly accessible to the scientific community. Its organizers anticipate that FaceBase will have a prototype ready within the next year and a fully functioning database soon after.
"The FaceBase project is the right initiative at the right time," said Francis Collins, M.D., Ph.D., director of the National Institutes of Health. "The scientific tools and enthusiasm now exist to systematically define from A to Z a developmental process that profoundly shapes our identities as human beings. The next several years will be very exciting indeed."
Scientists long have marveled at how bud-like colonies of embryonic cells form in the first weeks of pregnancy near the primitive mouth and, in communication with adjacent tissue, churn out a highly specialized work force of derivative cells. These cells make up the bone, cartilage, ligament, nerve, and soft tissue that parents will recognize several months later on their first sonogram as their baby's head.
But between the first embryonic cells and the first sonogram, profound developmental questions persist. On the molecular level at which nature works, scientists have lacked a comprehensive parts list of the genes and proteins that drive these embryonic cells to do great things. They also need a better handle on the cellular dynamics that drive the process of tissue formation. This includes primarily the communal crosstalk among dividing cells that prompt them to migrate, populate, and settle into compartments, and synchronize their self assembly into intricate, three-dimensional patterns as dissimilar as a salivary gland and the temporal bone of the skull.
On a macro level, researchers confront equally profound questions. Why does each tissue and structure of the human face form in exactly the right place? How do they orchestrate their three-dimensional growth and then integrate seamlessly into a single composite structure that is the human head?
Historically, it fell to individual research laboratories, particularly those interested in genetics and developmental biology, to try to answer these questions. These labs have made remarkable progress; but, as time and science have marched ahead, it's become clear that to answer such profound questions, scientists must better coordinate their efforts and draw on the talents and expertise of colleagues skilled in other scientific disciplines.
The NIDCR, recognizing this research need, began organizing FaceBase two years ago. The initiative builds on two broad organizing principles. The first is to encourage the formation of multidisciplinary research teams and then a higher level of integration into a consortium with the idea being that not every research problem will be or even can be solved with a single approach. Most will require a range of tools and expertise, allowing a more powerful research synergy to peel away the many layers of biological complexity and reach the essence of the question. The 11 grants announced today will support the FaceBase Consortium, a collection of collaborative research teams at various sites around the country.
The second is for each team to target its efforts at one specific aspect, or theme, of craniofacial development. This will allow the initiative to cast a more comprehensive research net that avoids duplication of effort. The research teams will coordinate their efforts through a designated FaceBase hub that manages data integration, data sharing and organizational needs.
"The FaceBase initiative will start out with a tight focus on the development of the mid-face region," said Lawrence Tabak, D.D.S., Ph.D., the director of NIDCR. "But if this more coordinated, systems approach works well, it's very possible that the initiative can be expanded to focus on tooth development, salivary gland formation, and really any tissue of the craniofacial complex."
Another essential aspect of the initiative is the FaceBase database. It builds on the lessons learned of other biology-focused databases. But FaceBase must mold its content to the specific interests and needs of craniofacial researchers. That includes learning how best to house data on biochemical, molecular, genetic and imaging studies. It also includes learning how best to display thousands of visual images of tissue morphology, or shape, after a specific gene has been disrupted in zebrafish, mice, and other organisms, a standard approach to determine a gene's function. These images then will be linked to molecular data from other studies and these datasets will be made available to the scientific community. Assembling all of these features will take time.
Steven Scholnick, Ph.D., an NIDCR scientist who administers the FaceBase initiative, said the end result of the database and research consortia will be well worth the effort. "If you sketch out the whole consortium on paper, you can easily see how the projects are mutually reinforcing and how interconnecting all of these diverse sets of data can be useful to the entire craniofacial research community - individual labs won't have to each invent their own part of the wheel and can instead focus on the bigger, systems-level picture" he said. "It's even more exciting to think that this consortium can lead to collaborations we can't yet envision and that it could accelerate our efforts to help families with children born with craniofacial abnormalities."
The principal investigators on the FaceBase Consortium grants are:
- Jeffrey C. Murray, University of Iowa and Mary L. Marazita, University of Pittsburgh
FaceBase Management and Coordination Hub - Axel Visel, University of California-Lawrence Berkeley Lab
Genome-Wide Atlas of Craniofacial Transcriptional Enhancers project - Leah Rae Donahue and Stephen Murray, The Jackson Laboratories
Genetic Tools and Resources for Orofacial Clefting Research project - Scott E. Fraser, California Institute of Technology
Functional Analysis of Neural Crest and Palate: Imaging Craniofacial Development project - Linda Shapiro, University of Washington
Shape-Based Retrieval of 3D Craniofacial Data project
- David Clouthier and Kristin Bruk Artinger, University of Colorado, Denver; and John Postlethwait, University of Oregon
Identification of miRNAs Involved in Midfacial Development and Clefting project - Richard Spritz, University of Colorado
Genetic Determinants of Orofacial Shape and Relationship to Cleft Lip/Palate project - Steven S. Potter, Children's Hospital Medical Center of Cincinnati
Global Gene Expression Atlas of Craniofacial Development project - Terri H. Beaty, Johns Hopkins University
Oral Clefts: Moving from Genome-Wide Studies Toward Functional Genomics project - Yang Chai, University of Southern California
Research on Functional Genomics, Image Analysis and Rescue of Cleft Palate project - Mary L. Marazita and Seth Weinberg, University of Pittsburgh
3D Analysis of Normal Facial Variation: Data Repository and Genetics project
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