Harnessing biological diversity and machine learning to build a cell engineering toolbox
Name
jiang-kaiyi-phd-be-2025-thesis.pdf
Size
5.2 MB
Format
Adobe PDF
Checksum (MD5)
66497c1ce1f136296b6b39c0b207cecd
Author(s)
Jiang, Kaiyi
Advisor(s)
Abudayyeh, Omar
Gootenberg, Jonathan
Birnbaum, Michael
Date Issued
May 2025
Publisher
Massachusetts Institute of Technology
Abstract
The exploration of diverse biological systems has furnished the broad biomedical community with a multitude of valuable molecular tools over the past decades. These include the widely used CRISPR-Cas genome editing systems and synthetic therapeutic circuits for adoptive cell therapy, such as CAR-T circuits and synthetic Notch circuits. As gene and cell therapies progress into clinical stages, there is a pressing need for programmable control of cell functions and phenotypes to develop safer and more effective gene and cell therapies. Cell engineering requires precise control of cell states and cell fates, yet existing methods lack sensitivity and programmability. Here, I present an integrated molecular toolbox combining novel multi-omics sensors with a foundation protein engineering models to enable programmable cell control. In particular, reprogrammable ADAR Sensors (RADARS) allow conditional protein expression based on any combination of RNA transcripts, supporting applications such as cell-state recording and targeted ablation. Csx29, the first RNA-guided protease from type III-E CRISPR systems, forms the basis of a post-translational protein circuit for RNA sensing. In addition, I characterized Fanzor, the first eukaryotic RNA-guided DNA nuclease. Lastly, to accelerate protein engineering, I developed EVOLVE-Pro, a state-of-the-art AI-driven model for rapid in silico evolution of protein activity. Together, these advances illuminate new avenues for decoding cell-state dynamics, engineering multi-omics perturbations, and developing therapeutic strategies for complex diseases.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
In Copyright - Educational Use Permitted
Copyright retained by author(s)
Persistent DSpace Link
