The Physician Researcher and FD/MAS as a Spectrum

Kelly Wentworth, M.D.is an assistant professor in the School of Medicine at the University of California, San Francisco and one of the four researchers to receive a Team FD Million Dollar Bike Ride research grant in 2018. Her project year is nearly done, and her work in FD/MAS will continue. Dr. Wentworth was recently awarded an NIH K08 career development award which focuses on research training and career development, and which will support her continuing work on FD/MAS.

We caught up with Dr. Wentworth to understand her research and how the Million Dollar Bike Ride funding opened up a new, inter-lab collaboration for her. Here’s our conversation:

How did you become involved in rare bone disease research?

In addition to patient care, part of what I love about medicine is delving into the mechanisms of disease. Initially, when I finished my medical residency, my work primarily involved patient care.  However, I found that I really missed being in the lab. In 2014, I started my endocrinology fellowship at UCSF and joined the laboratory of Dr. Edward Hsiao, who has research expertise in FD/MAS and rare bone diseases.  Dr. Hsiao was really instrumental in encouraging me to pursue a career as a physician-scientist. I have been especially interested in FD research because there is so much about this disease that we don’t understand. And there is a great need to develop effective treatments for this disease.

The field has definitely grown over the last 10 years, and there have been many advances in understanding how the genetic changes lead to FD/MAS.  However, there is still much to learn. It is an exciting time to be a part of FD/MAS research!

Can you tell us more about what it means to be a physician-researcher? FDF partners with many researchers, some of whom have PhDs, but many have earned MDs. How has your medical training helped define your work?

Physician-scientists have a unique opportunity to bridge the gap between clinic and bench research. I see patients with FD in our clinic and have the opportunity to listen to their stories, concerns, and needs that are most important to them. These ideas then inform my work in the laboratory.  Every day that I am in the lab, I am thinking about the connection between the questions that I am seeking to answer in the laboratory, and what is important and meaningful to my patients.

Tell us about some of the questions you’ve been asking–FD/MAS is a complicated disease, what exactly does your study address?

It is a complicated disease! My research has focused on understanding the effects of the GNAS mutation in early development, as well as the effects of the disease on the craniofacial skeleton. I’ve also been developing the tools to develop better models of human FD/MAS in the lab.

And the head and face are such delicate and complicated areas to be affected by FD.

Yes, fibrous dysplasia in the craniofacial skeleton can lead to significant medical problems.  It can affect a person’s vision and hearing, the way they eat and enjoy food, and even their speech.  Additionally, craniofacial bones have a different embryologic origin than other bones in the body, which means that whether FD develops in the jaw or in the leg is decided at a very early time-point in development.

Fascinating, so can a person be affected from both embryonic origins, so both these craniofacial bones and the long bone? 

Yes.  Depending on when the mutation occurs, people can develop fibrous dysplasia in many different bones.

From my understanding of FD and MAS, the earlier it develops the more parts of the body are affected, in terms of number of bones and hormonal complications. Is that right?

We believe that the earlier the mutation occurs in development, the more organ systems that may ultimately be involved.  Since FD/MAS is a mosaic disease, not every cell in the body carries the mutation, but we believe that the more cells that carry the mutation, the more severe the clinical manifestations.  We consider FD/MAS to exist on a spectrum.

And your other research looks at this spectrum on a cellular level?

Our research project with the Team FD Million Dollar Bike Ride grant is to understand which cells in human FD bone lesions carry the GNAS mutation and how they may differ from cells that do not carry the mutation.

This is what makes it a mosaic disease–some cells carry the mutation and some don’t, right?

Yes- that can be the case even within an FD lesion, not just from one area of the body to another. So we are using tissue samples from FD lesions that have been generously donated by patients undergoing surgery to help us better understand the difference between cells that carry the mutation and those that do not.

The community is obviously excited about all the great work the Million Dollar Bike Ride awardees do, but they’re anxious for answers too…

Right now we are in the data collection phase, but we are making significant progress.  Early on in the awarding process, another 2018 Team FD awardee, Dr. Fernando Fierro, and I realized our projects were complementary, and since then we have been collaborating and sharing resources. This has significantly strengthened each of our research projects and has allowed us to share a single patient cohort across different university settings.

Wow, that’s wonderful news. I know the research world can be very competitive, everyone going after the same funding and all, but the patient community all want forward progress. They want to know that the Million Dollar Bike Ride is making a real and critical difference.

Absolutely.  The Bike Ride funding is so important, as is collaboration within the research community. Our research would not be possible without the Million Dollar Bike Ride grant and by the opportunity to work with other researchers like Dr. Fierro. It has allowed us to ask important questions and generate initial data that will help us better understand FD/MAS. I’m really thankful for this opportunity from the Million Dollar Bike Ride and the FDF.

But at this point you’ve received bigger funding through the NIH grant, right?

I was fortunate to receive a K08 career development grant through the NIH/NIDCR. The generous support from the NIH and the MDBR will allow me to continue my research in FD and contribute to our knowledge about the disease. In turn, I hope to improve our ability to treat FD/MAS.

The FD/MAS community is thrilled that you’ve received further funding and that you’ll be continuing this work! We can’t wait to catch up and hear more as you progress.

Thank you for all of your support!