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Publications of the Week

Synthetic Gene Circuits for Cell State Detection and Protein Tuning in Human Pluripotent Stem Cells

By November 30, 2022No Comments

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This week we profile a recent publication in Molecular Systems Biology from the lab of Dr. Peter Zandstra (pictured, back row, far left) with key authors Drs. Laura Prochazka and Yale Michaels (back row, second from left).

Can you provide a brief overview of your lab’s current research focus?

My lab is focused on two main questions … understanding how organized tissue emerge from pluripotent stem cells and, focused on the emergence of the hematopoietic – or blood-forming – system, generating functional progenitor and mature cells, especially lymphoid cells from pluripotent stem cells. More information can be found here.

What is the significance of the findings in this publication?

This paper is significant for a number of reasons. First of all it is one of the first demonstration of more complex multi-step synthetic circuits being implemented into human PSC. This remains a key challenge for the field and as we get better at this many new opportunities will open up. Secondly it shows that we can design a cell sate specific sensor in stem cells and have the output response graded. This is important because this may allow the develop of sophisticated sense-and-respond circuits in stem cell derived cells, a key capability in the more precise treating of diseases of the immune system. Finally the work is an elegance demonstration of the model – design – test engineering cycle, communicating a robust implementation that others can build upon.

What are the next steps for this research?

Moving forward, the computational and genetic tools developed here can be applied to generate new customized circuits that control not only desired secreted factors, but also transcription factors, small regulatory RNAs and other signaling and gene expression regulators from desired cell states or developmental stages. Our circuits, in combination with micropatterning, gastruloid, or organoid technologies, open the door to gain new insights into molecular mechanisms that guide pattern formation and other fundamental processes during early development or organogenesis. Additionally, our circuits can be applied to targeted killing of undesired cell types during differentiation, cell state tracking, re-enforcement (or lock-in) of desired cell states, direct conditional cell reprogramming in vitro and in vivo, and conditional production of therapeutic agents from hPSC-derived cell products.

If you’d like to mention your funding sources, please list them.

Wonderful to acknowledge the University of Toronto’s Medicine by Design initiative, which received funding from Canada First Research Excellence Fund (CFREF) (MPDF-2017-01), CIHR, Canada Research Chairs program,  Swiss National Science Foundation, Royal Academy of Engineering and Michael Smith Foundation for Health Research.

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