Dr. Levi, can you please introduce us to your team and provide some background on your work history leading up to your current work on FOP?
I am a clinician scientist, Director of the Burn/Wound and Regenerative Medicine Laboratory, Associate Burn Director and Assistant Professor in the Department of Surgery at the University of Michigan.
Yuji Mishina, PhD, is a Professor in Biologic and Materials Sciences at the University of Michigan School of Dentistry and a central mentor and collaborator in our group. He is world renown for his work on bone morphogenetic protein signaling.
Also on our team at the Burn/Wound and Regenerative Medicine Laboratory at the University of Michigan are:
- Shuli Li, PhD, Senior Scientist
- John Li, MD, Postdoctoral Fellow
- Serra Ucer, PhD, Postdoctoral Fellow
- Kaetlin Vasquez, Laboratory Manager
We have been working together for several years to better understand the interaction between inflammatory cells and stem cells. Specifically, we are interested in the effect of circulatory myeloid cells on tissue resident stem cells.
I initially became interested in heterotopic ossification (HO) as this is a frustrating and debilitating problem that I kept seeing clinically as a burn and reconstructive surgeon. I was especially frustrated that some patients I took care of could not heal their fractures, and yet here was a group of patients who were forming excessive bone where we did not want it to form. Even more frustrating was the fact that, even after surgically removing this bone, patients still had functional deficits and the bone could recur. This initial frustration inspired me to try to find a solution to this debilitating process. Luckily, there were several bright minds at Michigan also working on better understanding this process. Dr. Yuji Mishina developed the first animal model of BMP mediated heterotopic ossification that was the standard model for FOP. Dr. Mishina then put me in touch with Ernestina Schipani, MD, PhD, University of Michigan, who is an expert in hypoxic signaling as well as Paul Yu, MD, PhD, Brigham and Women’s Hospital, Harvard Medical School. These relationships, in addition to meeting Betsy Bogard with the International FOP Association, helped jump-start my career as a clinician scientist with a focus on heterotopic ossification and FOP.
What precipitated your interest in working to find treatments and a cure for FOP?
My interest in curing FOP was sparked by my interest in improving the quality of life and treatment of heterotopic ossification. As a burn and reconstructive surgeon, I see first-hand the severe disabilities caused by this destructive process. I am always frustrated as a clinician how a skin injury alone could cause abnormal bone to grow and cause severe restriction of joint range of motion in my patients. This initial frustration taught me that inflammation alone had to play a central role in heterotopic ossification and inspired me to try focus our laboratory efforts on mitigating this disease process.
the lives of these patients I began to work with Dr. Mishina at the University of Michigan. He had developed a mouse that was the gold standard for studying FOP and he put me in touch with leaders in the FOP field. Due to his guidance, as well as the mentorship of Dr. Schipani, I was encouraged to attend my first International FOP Association (IFOPA) meeting – the 2014 Drug Development Forum. At this meeting, I had the opportunity to meet several incredible people living with FOP, in addition to families that were supporting people living with FOP. I also had the opportunity to meet world-class physicians Fred Kaplan, MD, and Bob Pignolo, MD, PhD, who are dedicated to understand how to improve the treatment of these patients.
It was at that time that I realized that there were several important overlaps between patients with FOP and those patients I took care of with traumatic heterotopic ossification. I couldn’t help but think that the situation of heterotopic ossification that I was seeing in my trauma patients was similar to that of patients living with FOP. This led me to believe that the treatment strategies and diagnostic modalities I was working on in my trauma laboratory could be translated into improved care for people living with FOP.
Dr. Levi, have you met many people with FOP? Can you share a memorable anecdote about it? How did it affect you and your work?
I had the opportunity to meet people with FOP at IFOPA Drug Development Forums in 2014 and 2016. At these meetings, it was really eye-opening and inspiring to hear the challenges of people living with FOP. Learning more about their challenges has driven the focus of our laboratory. In fact, the first meeting that I attended I took diligent notes on several shortcomings in current diagnostic and treatment modalities and began to work on these vigorously in our laboratory. One thing I remember was patients telling me that they could always sense when a flare was coming on and they felt some sort of inflammation. This really led me to believe that there was a significant amount of overlap between the inflammation that causes heterotopic ossification in trauma patients and the heterotopic bone formation in people with FOP. This led us down an important line of investigation to better understand the role of hypoxic signaling and inflammation in patients with FOP. This work, in turn, led to several exciting findings around the efficacy of Rapamycin and therapies targeting hypoxia as potential treatment strategies. Additionally, after hearing that patients had a difficult time sitting in an MRI or CT scanner due to their FOP, we began working on several diagnostic modalities to improve visualization of early heterotopic lesions. Specifically, we have worked on an ultrasound device to improve early diagnosis as well as early diagnostics with salivary and serum biomarker analytics.
Dr. Levi, please share about the current FOP research work being done in your lab.
Our current FOP laboratory research focuses on early diagnostic modalities and ultrasound technologies. Additionally, our laboratory focuses on better understanding the role of inflammatory cells in the process of FOP. Recent collaboration with Dr. Mishina has led to an exciting drug development project targeting a new downstream pathway of bone morphogenetic protein (BMP) which is the primary pathway thought to cause HO. This pathway, called transforming growth factor beta one kinase (TAK1) holds promise in preventing HO formation while also being able to stimulate muscle regeneration when timed appropriately. Our research has allowed us to collaborate with Nathanael Gray, PhD, an expert in drug discovery at Dana-Farber Cancer. We are currently working together to help validate a TAK1 therapeutic candidate with improved efficacy and minimal off-target effects. If successful, these therapies could be trialed clinically to prevent HO in FOP patients.
Dr. Levi, what do you anticipate for the next 5 to 10 years of FOP research?
I anticipate over the next five or ten years of FOP research that we will have a standardized bedside diagnostic device that will allow for visualization of early flares and early heterotopic bone that would then allow the administration of a treatment that would limit the progression of the flare. I believe this therapy will be an anti-inflammatory treatment that will prevent the early pre-HO stages. My hope is to continue to collaborate with experts in the FOP field to vastly improve the lives of individuals living with FOP and pave the way for ongoing discoveries. I also hope that there will be increased visibility into the disease to drive better and quicker diagnosis and treatment.
Dr. Levi, can you share why you’re so passionate about FOP research?
Every day in our laboratory we begin by thinking about ways to improve patient care. As a clinician, the only way I believe we can be successful is if we can better understand and treat patients suffering from disease processes such as FOP. What really brought this close to home was having the McGuire family come to visit our laboratory. Getting to meet Natalie and the McGuire family was an incredible experience for our laboratory as we learned several important things about her challenges. Her enthusiasm and interest in our work and in becoming a physician in the future was extremely inspiring. She asked outstanding questions to our research team and her brother Keegan has volunteered in our laboratory despite a busy academic schedule. Interestingly, Natalie’s description of not being diagnosed until she was 11 years old, led us to undergo several lines of investigation around the role of sex steroids in heterotopic bone formation. I was bothered by the fact that even when she came to the University of Michigan, initially nobody properly diagnosed her. It took her dad Gary’s research via the internet to ultimately diagnose her FOP. Gary also asked extremely insightful questions and challenged us to continue to work on improving the care of people living with FOP. Even though FOP is rare, we strive to bring more light to the disease and help with better and earlier diagnoses and treatments than are currently available. As a surgeon scientist who treats patients with HO and surgically removes this destructive process, I know we can and will do better in the future for people living with FOP. We are inspired daily in our laboratory by the McGuire family and the incredible people living with FOP and their families to improve our understanding of this process and to enhance the diagnostic and treatment modalities available.
