Samantha Morris, PhD, Associate Professor of Medicine and Systems Biology at the Brigham & Women's Hospital and Harvard Medical School, is focused on understanding how cell identity can be manipulated via direct lineage reprogramming. She is leveraging her expertise in developmental biology to create new technologies that assess cell identity and ancestry throughout differentiation, at single-cell resolution. In combination with innovative transcription factor binding assays, Samantha aims to elucidate the molecular mechanisms driving cell fate conversion toward fully defined and functional cell types in order to generate cells that can improve understanding of developmental mechanisms as well as be used for cellular therapies for damaged or dysfunctional tissues.

Advances over the past half-century, such as nuclear transfer and factor-mediated reprogramming, have revealed the remarkable plasticity of cell identity. ‘Direct lineage reprogramming’ aims to directly transform cell identity between fully differentiated somatic states via the forced expression of select transcription factors (TFs). Using this approach, fibroblasts have been directly converted toward many clinically valuable cell types. However, existing protocols are highly inefficient; only a fraction of cells are converted, and many of the converted cells remain developmentally immature or incompletely specified, drastically limiting their usage for therapeutic application, disease modeling and drug screening. Why is direct reprogramming inefficient, and why are the resulting cells incompletely converted and developmentally immature? How can engineered cells be directed more efficiently toward defined identity and functionality? To answer these questions, we use fibroblasts reprogrammed into induced endoderm progenitors (iEPs) as our model system. Reprogramming occurs via a prototypical protocol, driven by expression of FoxA pioneer TFs with their cofactor, Hnf4a, yet the inefficiency of reprogramming and heterogeneity of cells generated have precluded systematic mechanistic analysis. To overcome these challenges, we have developed novel technologies to permit single-cell lineage tracing throughout reprogramming, site-specific temporal recording of TF-binding, and analysis of differentiation and resulting cell function within a novel in vitro organ regeneration model. Together, these goals are broadly applicable to the engineering and assessment of any cell type via any route and will provide critical insight into how to improve the efficiency of cellular reprogramming, and the fidelity of differentiation to target cell identity.

Before returning to Boston in 2024, Samantha Morris spent nine years at Washington University School of Medicine, St. Louis, USA.  As a postdoctoral fellow with Magdalena Zernicka-Goetz in Cambridge, UK, her work on early mammalian cell fate plasticity spurred an interest in manipulating cell fate for therapeutic purposes.  In pursuit of this, Samantha joined the laboratory of George Daley at Boston Children’s Hospital and Harvard Medical School, where she focused on the computational analysis of gene regulatory networks to dissect and engineer cell identity. 

Morris Lab