Medical applications of synthetic gene circuits and switches
Wong, Meng Lai Nicole
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Synthetic biology enables us to create artificial systems using existing biological components, allowing for an exertion of control over the system so that we can further understand how these components interact or bestow them with new capabilities. A multitude of such applications have emerged in recent decades, among them the introduction of protein chimeras and genetic circuits to cells that can be used to accelerate the development of medical treatments and make them safer. T cell immunotherapy is an example of such a technology, and has shown promising results in the treatment of various cancers. However, a persisting obstacle is the inability to control the activity of these engineered cells, as they can become overactive or display off-target activities. We have developed two approaches for controlling T cell activity: a dual small molecule gated ZAP70 switch, and a collection of drug-inducible chimeric antigen receptors (CARs) encompassing the NS3 protease domain. These artificial components allow for increased regulation over T cell therapy and can potentially make T cell therapy safer in the clinic. In addition to improving the safety of clinical treatments, engineered mammalian cells can also act as pathway-sensitive reporters for use in the discovery of gene and drug targets in large-scale screens. However, in traditional compound screens, temporally transient and weak responses may not be detected. Additionally, the decision of what constitutes a “hit” cell population in genome-wide screens can be relatively arbitrary, and thus key target genes could be missed. To address this, a recombinase-based circuit was developed that provides cells with memory, enhanced sensitivity, and an analog-to-digital readout. This reporter facilitates the screening process and enhances both drug and genome-wide screens.
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