Mouse Models, Research, and Hope
We had the pleasure of interviewing Yingzi Yang, Ph.D., Associate Dean for Research and Professor of Developmental Biology at the Harvard School of Dental Medicine. Dr. Yang is a leading scientist/researcher in skeletal biology and genetic disease studies and the recipient of a Team FD/MAS Million Dollar Bike Ride award.
Dr. Yang received her B.S. at Fudan University in Shanghai, China. Her Ph.D. in molecular biology is from Weill Medical College, Cornell University.
When not busy in the lab or lecture hall, Dr. Yang is a reader and a gardener. She also enjoys walking along the Charles River or the Boston seashore.
After earning her Ph.D., Dr. Yang discovered her interest in the molecular workings of the skeleton. She conducts research in cell communication in embryonic development and physiological functions of the skeleton and liver. Her investigations use mouse models, which allow the study of diseases—like fibrous dysplasia—in order to better understand the disease process without harming a human subject.
How does your research further our understanding of fibrous dysplasia and uncover promising paths to future treatments?
We have a long-standing interest in laying a foundation for future cures and treatment of fibrous dysplasia (FD) by collaborating with physicians and generating appropriate mouse models. We were the first to show that sustained high Wnt signaling in FD patient bone marrow stromal cells (BMSCs) is a key molecular mechanism causing bone overgrowth and poor ossification (Regard et al., PNAS 2011).
Can you give a quick overview of a normal workday?
I always come to my office early in the morning. I work at the computer and talk to people in the lab every day, providing research guidance at different levels. I also spend time teaching students, meeting and talking to my collaborators and colleagues and presenting our research results at scientific conferences.
Please explain your research in more detail.
In our recently published work, we have successfully created the first conditional “knock-in (KI)” mouse line Gnasf(R201H) in which the FD/MAS mutant GαsR201H can be expressed from its endogenous genetic locus with temporal and tissue specificity upon Cre induction (Khan, PNAS 2018}. Using this novel mouse line, we have found that Cre-induced Gnas FD mutant expression in early osteochondral progenitors, osteoblast cells or BMSCs recapitulated FD features. Furthermore, Wnt/β-catenin signaling was sustained at a higher level in the FD mutant mouse bone and BMSCs as we have found in the FD human tissue previously.
Importantly, the mouse models we have established allowed us to test pharmacological inhibition of Wnt/β-catenin signaling, which partially rescued osteoblast differentiation and bone ossification that were blocked by expressing GαsR201H (Khan et al., PNAS 2018; Xu, 2018, Bone Research). Our unpublished preliminary results also showed that Yap protein, which can regulate osteoblast differentiation, was inhibited by GαsR201H expression in bone tissues. These findings provide another opportunity to further the understanding of the disease and uncover promising roads to future treatments.
Science is often built from the failure of experiments. How do you recover from failure in the lab?
Sit back and identify where the problems may be, solve the problems with rigorous troubleshooting procedures, and start all over again.
How does the patient image or patient voice figure into your work?
Helping the patients by finding a cure or reducing their pain is a strong motivation in our research.
What do you want fibrous dysplasia patients and families to understand about research?
In terms of FD research, I want patients and families to understand why basic research is so important in disease studies. [Editorial Note: Basic research is the foundation of future treatments.] Also, it is helpful to have some knowledge of the detailed requirements of laboratory research, including the necessity and methods of animal models, cell cultures, and molecular biology.
What does the near future hold for treatments and cures for fibrous dysplasia? Is there a success in another disease that provides hope?
I am quite confident that we will be able to find ways to treat or reduce the symptoms of FD patients. We are also studying a related disease, heterotopic ossification caused by loss of Gnas function, where we have successfully identified targets and reagents that can be used for a cure test.
Research can be expensive: What costs are related to advanced research? Can you break it down so donors and funders see where the money is needed?
Research is truly expensive. A National Institutes of Health (NIH) project typically funds $250,000/year for 5 years. Among these, about $180,000 will be used for the personnel costs (15% of my salary, 100% of two postdoctoral fellows or students), $20,000 will be used for animal studies and $50,000 for general lab consumables.
What would you like donors and sponsors to understand about research?
We need more support for FD research.
Special thanks to Caroline Fuchs, CAE for this spotlight.