Cell fate is flexible
The generation of clinically relevant cells, such as neurons, cardiomyocytes, and hepatocytes, in vitro offers potential for regenerative therapy and permits disease modeling, toxicology testing, and drug discovery. Cell differentiation had long been thought a unidirectional process toward restricted potential and increased specialization. In the past half-century, this has been challenged: Mature somatic cells can be returned to a pluripotent state, and subsequently differentiated to desired cell types. Alternatively, mature cells can be ‘directly converted’ from one mature state to another via transcription factor overexpression, bypassing pluripotency. Many approaches are employed to generate defined fate in vitro, however, the resultant cells often appear developmentally immature or incompletely specified, limiting their utility.
The challenges of assessing and engineering cell identity
The evaluation of cell fate has been confounded by the lack of any systematic means by which to assess the fidelity of engineered cells. We were involved in the development of ‘CellNet’, a network biology-based computational platform that accurately evaluates cell fate through gene regulatory network reconstruction and generates hypotheses for improving cell differentiation protocols (see Cahan et al., Cell, 2014, and Morris et al., Cell, 2014). Using this platform we surveyed a range of engineered cells and found that cells derived via directed differentiation more faithfully recapitulated target cell identity than cells generated by direct conversion. These directly converted cells commonly failed to silence expression programs of the original cell type, and illicit gene expression programs were frequently induced. Employing induced endoderm progenitors (iEPs) generated from fibroblasts as a prototypical conversion, our computational and functional analyses showed that iEPs behave as embryonic progenitors with the potential to functionally engraft both the liver and colon. We found that these engineered cells resembled mature colonic epithelium after transplantation into the colon niche.
Now, we are investigating how the transcription factors utilized in these conversion protocols impact the GRN of the host cell to drive changes in cell identity. We are particularly interested in pioneer factors, capable of remodeling chromatin and often re-purposed during development. To study the mechanism of conversion we use a combination of transcriptional, epigenetic, and functional analyses. This understanding will help us guide the activity of conversion factors and unlock further progenitor potential of engineered cells. In addition, this line of investigation will be broadly applicable to the cell fate engineering field and may also shed light on the activity of transcription factors during development.
Single-cell mapping of lineage and identity in cell fate reprogramming
Recently, we have revealed further mechanisms of reprogramming to iEPs. Successful reprogramming is a rare event, thus it had remained a challenge to isolate and analyze the few iEPs emerging from fibroblasts. High-throughput single-cell RNA-sequencing has enabled this heterogeneity to be deconstructed, although lineage relationships between cells were lost, making interpretation of the data a challenge. To overcome this, we have developed a straightforward, high-throughput cell tracking method, ‘CellTagging’ (see Biddy et al., Nature, 2018; Kong et al., Nature Protocols 2020). Sequential lentiviral delivery of heritable random unique molecular indexes, CellTags, permits the construction of multi-level lineage trees. CellTagging and longitudinal tracking of fibroblast to induced endoderm progenitor reprogramming revealed two distinct trajectories: one leading to successfully reprogrammed cells, and one leading to a ‘dead-end’ state, paths determined in the earliest stages of lineage conversion. We found that expression of a putative methyltransferase, Mettl7a1, is associated with the successful reprogramming trajectory; adding Mettl7a1 to the reprogramming cocktail increased the yield of induced endoderm progenitors.
We continue to focus on the development of new experimental and computational single-cell technologies to track cell identity (see Guo et al., Genome Biology, 2019, Kamimoto et al., BioRxiv, 2020, Kong et al., BioRxiv, 2020). Our main focus is to apply these tools to a broad range of reprogramming systems to uncover the general mechanisms of cell fate conversion. In addition, we are tracking the maturation of iEPs in the intestine at the single-cell level following transplantation. Mapping these in vivo differentiation steps will help guide maturation in vitro and also assist in identifying factors to promote liver repopulation and maturation. This line of investigation will aid in answering important questions about silencing of the donor cell program and establishment of the target cell GRNs.
Education and Professional Experience
7/15-present Assistant Professor, Department of Genetics, Department of Developmental Biology, Washington University School of Medicine, St. Louis, USA
11/11-7/15- Postdoctoral Fellow, Boston Children’s Hospital, Harvard Medical School, USA Laboratory of Professor George Daley, MD, PhD
07/07-10/11 Postdoctoral Fellow, Gurdon Institute Department of Physiology, Development and Neuroscience, University of Cambridge, UK Laboratory of Professor Magdalena Zernicka-Goetz, PhD
10/02-09/06 PhD, Department of Oncology Clare College, University of Cambridge, UK Laboratory of Professor Shin-ichi Ohnuma, PhD
9/99-7/02 Bachelor of Science, Department of Biochemistry Imperial College of Science, Technology, and Medicine, University of London Graduated First Class, with honor
Honors and Awards
2021 New York Stem Cell Foundation Robertson Investigator
2020 2020 Sloan Research Fellowship in Computational and Evolutionary Molecular Biology
2020 Washington University School of Medicine 2020 Distinguished Investigator Award
2019 Allen Distinguished Investigator Award
2019 Cell Stem Cell, ‘Best of 2018’ for Wu et al., “Comparative Analysis and Refinement of Human PSC-Derived Kidney Organoid Differentiation with Single-Cell Transcriptomics”
2019 St. Louis Academy of Science Innovation Award
2017 Vallee Foundation Young Investigator Award
2014 Sanofi-Cell Research’ Outstanding Review Article Award 2013′, for Morris and Daley, “A
blueprint for engineering cell fate: current technologies to reprogram cell identity.”
2013 Alex’s Lemonade Stand Young Investigator Award
2013 Cell Reports, ‘Best of 2012’ for Morris et al., “Developmental plasticity is bound by Fgf and Wnt signaling pathways”
2009 Runnström Medal for Wenner Gren Institute Lecture, Stockholm University
2009 Gurdon Institute, University of Cambridge, Research Prize
2005 Department of Oncology, University of Cambridge, Research Prize
2000 Eric Potter Clarkson prize for best use of intellectual property
1. Minn KT, Fu YC, He S, Dietmann S, George SC, Anastasio MA, Morris SA*, Solnica-Krezel L*. High-resolution transcriptional and morphogenetic profiling of cells from micropatterned human embryonic stem cell gastruloid cultures. Elife. 2020 Nov 18;9:e59445. *co-corresponding authors.
2. McCoy MJ, Liu Y, Cates K, Abernathy DG, Zhang B, Liu S, Gontarz P, Kim WK, Chen S, Kong W, Gabel HW, Morris SA, Yoo AS. Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNA. Cell Stem Cell. 2020. Sept 21.
3. Li Y, Kong W, Yang W, Okeyo-Owuor T, Patel RM, Casey EB, Morris SA*, Magee JA*. Single cell analysis of neonatal HSC ontogeny reveals gradual and uncoordinated transcriptional reprogramming that begins prior to birth. Cell Stem Cell. 2020. Aug 20. *co-corresponding authors.
4. Moudgil A, Wilkinson MN, Chen X, He J, Cammack AJ, Vasek MJ, Lagunas T, Qi Z, Morris SA, Dougherty, JD, and Mitra RM. Self-reporting transposons enable simultaneous readout of gene expression and transcription factor binding in single cells. Cell. 2020 Jul 18.
5. Kong W, Biddy BA, Kamimoto K, Amrute JA, Butka EG, Morris SA. CellTagging: combinatorial indexing to simultaneously map lineage and identity at single-cell resolution. Nature Protocols. 2020. Feb 12.
6. Seiler KM, Waye SE, Kong W, Kamimoto K, Bajinting A, Goo WH, Onufer EJ, Courtney C, Guo J, Warner BW*, Morris SA*. Single-Cell Analysis Reveals Regional Reprogramming during Adaptation to Massive Small Bowel Resection in Mice. Cell Mol Gastroenterol Hepatol. 2019. Jun 10. *co-corresponding authors.
7. Guo B, Kong W, Kamimoto K, Rivera-Gonzalez GC, Yang X, Kirita Y, Morris SA. CellTag Indexing: a genetic barcode-based multiplexing tool for single-cell technologies. Genome Biology. 2019 May 9;20(1):90
8. Biddy BA, Kong W, Kamimoto K, Guo C, Waye SE, Sun T, Morris SA. Single-cell mapping of lineage and identity in direct reprogramming. Nature. 2018 Dec;564(7735):219-224.
9. Morris SA*, Cahan P*, Li H*, Zhao AM, San Roman AK, Shivdasani RA, Collins JJ, Daley GQ. Dissecting engineered cell types and enhancing cell fate conversion via CellNet. Cell. 2014; 158(4):889-902. *co-first author.
10. Cahan P*, Li H*, Morris SA*, Lummertz da Rocha E, Daley GQ, Collins JJ. CellNet: network biology applied to stem cell engineering. Cell. 2014; 158(4):903-915. *co-first author.
11. Morris SA, Guo Y, Zernicka-Goetz M. Developmental plasticity is bound by pluripotency and the Fgf and Wnt signaling pathways. Cell Reports. 2012; 2(4):756-65.
12. Morris SA, Grewal S, Barrios F, Patankar SN, Strauss B, Buttery L, Alexander M, Shakesheff KM, Zernicka-Goetz M. Dynamics of anterior-posterior axis formation in the developing mouse embryo. Nature Communications. 2012; 3:673.
13. Morris SA, Teo RT, Li H, Robson P, Glover DM, Zernicka-Goetz M. Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107(14):6364-9.