Thorold Theunissen, PhD

Research interests

Embryonic stem cells (ESCs) have the ability to self-renew indefinitely while maintaining the capacity to differentiate into all cell types found in the body. Due to these unique properties, ESCs have become a versatile tool in wide-ranging biomedical applications, from disease modeling to toxicology testing to clinical trials. In addition, the discovery of induced pluripotent stem cells (iPSCs) provides new possibilities to model complex genetic disorders and a source of autologous cells for transplantation. However, major challenges must be overcome before human ESCs and iPSCs can be used in a realistic way in regenerative medicine. The main challenge is that current human ESCs and iPSCs do not resemble the ground state “naive” pluripotent cells found in the blastocyst, but instead are more similar to “primed” precursors that arise after the embryo has implanted. The naive state is signified by an unrestricted developmental potential, whereas the primed state displays repressive chromatin features and lineage priming.

While naive stem cells can be derived in rodents, their isolation has long remained elusive in the human system. The discovery of naive human pluripotent stem cells has broad implications for biomedical research. First, naive human cells may offer an enhanced starting point for differentiation into disease-relevant cell types, overcoming the heterogeneity frequently observed in current human ESCs and iPSCs. Second, the isolation of naive human cells may provide a cell culture system to study epigenetic mechanisms of human preimplantation development that cannot be investigated in primed cells. Such studies are essential to help understand the high percentage of unexplained pregnancy loss. Third, naive induction may correct the erosion of dosage compensation prevalent in female human ESC and iPSC lines, enabling faithful in vitro modeling of X-linked diseases. Fourth, the injection of naive human cells into the blastocyst of an animal host may allow the generation of interspecies chimeras, providing a novel paradigm to study functional cells derived from patient iPSCs in vivo.

Our research is focused on three key questions:

1. What are the signaling requirements for naive pluripotency, and how can we manipulate these pathways to create an optimal culture environment for deriving and maintaining human ESCs and iPSCs?
2. What are the major transcriptional and epigenetic mechanisms underpinning the self-renewal and lineage commitment of pluripotent cells in the embryo and the culture dish?
3. Can we leverage the unique properties of distinct pluripotent stem cell states to better model early human development and disease?

Education and Professional Experience

Assistant Professor, Washington University School of Medicine, 2017-Present

Postdoctoral Fellow, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 2012-2017

Ph.D., Biochemistry and Stem Cell Biology, University of Cambridge, 2008-2011

M.Phil., Developmental Biology, University of Cambridge, 2007-2008

A.B., Biology, Harvard University, 2003-2007

Research Experience

Postdoctoral Fellow in the Laboratory of Rudolf Jaenisch, M.D. Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 2012-2017. Stem cell biology, developmental biology and epigenetics.

Graduate Student in the Laboratory of José Silva, Ph.D. Wellcome Trust Center for Stem Cell Research, Department of Biochemistry, University of Cambridge, 2008-2011. Mechanisms of induced pluripotency: role of the homeodomain transcription factor Nanog.

Undergraduate Thesis Research in the Laboratory of Stuart Orkin, M.D. Division of Hematology/Oncology, Boston Children’s Hospital and Howard Hughes Medical Institute, 2005-2007. Expanding the transcription factor network in mouse embryonic stem cells: the role of Dax1

Herchel Smith Internship in the Laboratory of Christine Mummery, Ph.D. Hubrecht Institute, Utrecht, The Netherlands, Summer 2005. Development of regenerative therapy for damaged cardiac tissue.

Honors and Awards

NIH Director’s New Innovator Award (DP2), 2019

Shipley Foundation Program for Innovation in Stem Cell Science Award, 2019

Edward Mallinckrodt Jr New Investigator Award, 2019

Sir Henry Wellcome Postdoctoral Fellow, 2012-2017

Cambridge Philosophical Society, elected in 2008

Wellcome Trust Ph.D. Studentship, 2007-2011

Summa Cum Laude, Harvard University, 2007

Phi Beta Kappa, Harvard University, elected in 2007

John Harvard Scholarship, 2006

Selected publications

• Dong, C., Fischer, L.A. and T.W. Theunissen (2019). Recent insights into the naïve state of human pluripotency and its applications. Exp. Cell Res., 385:1, 111645.
• Theunissen, T.W. and R. Jaenisch (2017). Mechanisms of gene regulation in human embryos and pluripotent stem cells. Development, 144: 4496-4509.
• Theunissen, T.W.*, Friedli, M.*, He, Y.*, Planet, E., Oneil, R., Markoulaki, S., Pontis, J., Wang, H., Iouranova, A., Imbeault, M., Duc, J., Cohen, M.A., Wert, K.J., Castanon, R.G., Zhang, Z., Huang, Y., Nery, J.R., Drotar, J., Lungjangwa, T., Trono, D., Ecker, J.R. and R. Jaenisch (2016). Molecular criteria for defining the naive human pluripotent state. Cell Stem Cell 19, 1-14. *Co-first author.
• Theunissen, T.W.*, Powell, B.E.*, Wang, H.*, Mitalipova, M., Faddah, D., Maetzel, D., Ganz, K., Shi, L., Stelzer,Y., Zhang, J., Lungjangwa, T., Imsoonthornruksa, S., Rangajaran, S., Fan, Z.P., Young, R.A., Gray, N., and R. Jaenisch (2014). Systematic identification of culture conditions for induction and maintenance of naive human pluripotency, Cell Stem Cell 15, 471–487 (2014). *Co-first author.
• Theunissen, T.W. and R. Jaenisch (2014). Molecular control of induced pluripotency. Cell Stem Cell 14, 720-734.

• Costa, Y.*, Ding, J.*, Theunissen, T.W.*, Faiola, F.*, Hore, T.A., Shliaha, P.V., Fidalgo, M., Saunders, A., Lawrence, M., Dietmann, S., Das, S., Levasseur, D.N., Li, Z., Xu, M., Reik, W., Silva, J.C.R.* and J. Wang* (2013). NANOG-dependent function of TET1 and TET2 in establishment of pluripotency, Nature 495, 370-4. *Co-first author.
• Theunissen, T.W. and J.C.R. Silva (2012). Somatic cell reprogramming: role of homeodomain protein Nanog, in Stem cells and Cancer Stem Cells: Therapeutic Applications in Disease and Injury. M.A. Hyat (Ed.) Springer 6, 377-384.
• Theunissen, T.W., Costa, Y., Radzisheuskaya, A., van Oosten, A.L., Lavial, F., Pain, B., Castro, L.F.C., and J.C.R. Silva (2011). Reprogramming capacity of Nanog is functionally conserved in vertebrates and resides in a unique homeodomain. Development 138, 4853-4865.
• Theunissen, T.W. and J.C.R. Silva (2011). Switching on pluripotency: a perspective on the biological requirement of Nanog. Philosophical Transactions of the Royal Society B: Biological Sciences 366, 2222-2229.
• Theunissen, T.W., van Oosten, A., Castelo-Branco, G., Hall, J. Smith, A., and J.C.R. Silva (2011). Nanog overcomes reprogramming barriers and induces pluripotency in minimal conditions, Current Biology 21, 65-71.

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