What is the current focus of your research, and what do you find most rewarding about your work?
As a physician-scientist at the University of Michigan, my laboratory applies epigenetic research to two themes: ocular cancers and stem cell biology. In 2009, when I began my work in ocular epigenetics at Harvard, nothing was known about histone methylation in the mammalian retina or in eye disease. My seminal work defined the “white space” of how epigenetic proteins known as histone methyltransferases (HMTs) regulate mammalian eye development and human eye disease. My research links HMT dysfunction to eye disease for the first time. Through national and international collaboration to secure rare eye tumors (e.g. U. Sao Paulo, Brazil), my lab identified various HMTs, and other proteins as biomarkers or therapeutic targets in retinoblastoma, medulloepithelioma, orbital basal cell carcinoma, intraocular and orbital lymphomas, and squamous cell carcinomas of the ocular surface. No other investigator has defined the targetable cancer genome of so many ocular cancers. In our second research theme, we discovered that the chromatin modifier WDR5 directly interacts with transcription factors (TFs) p53 to regulate retinal fate choice. Our work introduces the transformative idea that interplay of ubiquitous chromatin modifiers and TFs at a critical developmental window triggers retinogenesis. Our studies alter key concepts related to congenital retinal defects in p53-associated syndromes, use of p53 mutant human pluripotent stem cell-derived retinal cells for transplants, and potential off-target effects of ‘therapeutic’ WDR5 inhibitors, which is being developed in a $1 billion program.
What led you to become a scientist and to stem cell research?
I was an undergraduate at the University of Wisconsin-Madison in 1998, just as the first report of successful culture of human embryonic stem cells was published by UW-Madison scientist James Thomson. It excited me that you could study human cells in transient precursor states you could never isolate before, and in that way learn about human development, as well as chart new paths for cell therapy for neurodegenerative and age-related diseases, drug screening, and disease modeling. This also inspired me to go to medical school where I thought I could be a physician-scientist and translate laboratory advances to patient care. I devoted my scientific work to retinal development and disease, in part because retinal degenerative diseases, like macular degeneration, are so common, but we lack the means to regenerate the lost retinal cells. As a result, there are no therapies that restore sight in forms of macular degeneration in which retinal cells are lost (e.g. dry macular degeneration, the most common form). And the only time these retinal cells multiply and grow is during the developmental period and so perhaps there are principles from development an stem cell biology that can inform us toward to therapies for these blinding diseases.
What is the most exciting aspect of your work?
I enjoy the feeling, perhaps hope, of “rewriting the textbook” on how the retina develops from pluripotent stem cells. For instance, classically the eye field (precursor to the retina) is formed from eye field transcription factors (EFTFs), which are expressed at a specific time and place. However, in this context our work has revealed an unexpected function of ubiquitously expressed epigenetic genes: these genes control the EFTFs themselves in a temporal way. Thus ‘housekeeping’ epigenetic genes, expressed everywhere and at all times, can have very specific functions at certain timepoints in development. Another area that is exciting is being the retina surgeon for a clinical trial that uses a first-in-human retinal cell transplant to try to improve vision in advanced macular degeneration.
What guidance would you share in talking with trainees interested in pursuing your area of research?
Do something you are passionate about, don’t be afraid to fail, and remember that being able to successfully communicate even arcane research activities to the general public and patients is key to having people understand why you are so passionate about the work you do.
Do you have any mentors or individuals who have inspired you in your stem cell work?
Sally Temple, Robin Ali, Jeff Stern, Ron McKay, Su-Chun Zhang, Ian Duncan, Diane Krause, and Dong Feng Chen.
How do you spend your free time?
With my wife and two young kids, and increasingly with the pandemic, a close knit group of neighbors.
What is something your peers would be surprised to learn about you?
I know a lot about elapids (a family of venomous snakes, including cobras, in Asia, Africa Australia, and in the oceans)
What do you most value about your membership with the ISSCR?
The ability to interact with like-minded colleagues, trainees, and giants in the field… most of whom want to make a difference in human health with their work. I also respect the advocacy efforts of ISSCR to ensure our field has access to resources and cells necessary to do research and make translational advances.