Advanced engineered cell therapies are an area of great promise for treatments of diseases ranging from cancer to diabetes. In order to be useful in the clinic, genetic control over the cells is needed. Now, researchers have created a system for gene editing that can be triggered by a compound found in green tea.

The engineered cells, which successfully treated diabetes in mice and macaque monkeys that drank green tea, could potentially be used as a remotely controlled and easy-to-follow therapy for diabetes in humans. They could also be used for various other applications, such as guiding CRISPR gene editing and conducting digital computations.

The work is published in a paper titled “A green tea–triggered genetic control system for treating diabetes in mice and monkeys” in Science Translational Medicine.

The authors noted that the translation of many promising cell-based technologies into the clinic is currently limited by a lack of remote-control inducers that are safe and can be tightly regulated. In recent years, researchers have made progress in refining the control of cell therapies, which have shown promise for diseases such as cancer. Cell therapies often use a compound to trigger cells to secrete a specific therapeutic, but existing triggers such as antibiotics can have side effects or may be unsafe for long-term use.

Authors Jianli Yin and Haifeng Ye, PhD [East China Normal University]
Seeking a safer trigger, Jianli Yin and colleagues in the lab of Haifeng Ye, PhD, professor in the school of Life Sciences in East China Normal University, turned to green tea, a popular beverage around the globe that contains a metabolite called protocatechuic acid (PCA). The team developed a control system by engineering cells to respond to PCA. They constructed multiple genetic control technologies that could toggle a PCA-responsive on/off switch based on a transcriptional repressor from Streptomyces coelicolor and showed how these technologies could be used as implantable biocomputers in live mice to perform complex logic computations that integrated signals from multiple food metabolites.

The team wrote that they demonstrated the use of the PCA on/off switch in three major bioengineering areas: in CRISPR-Cas9 systems for genome engineering, in controllable engineered cell biocomputer implants in live mice, and in controllable engineered cell-based drug delivery systems for treating diabetes in both mouse and monkey models.

The team demonstrated that PCA-controlled switches can be used for guide RNA expression–mediated control of the CRISPR-Cas9 systems for gene editing and epigenetic remodeling. The scientists were able to use their PCA-responsive cells to perform more targeted CRISPR gene editing and as “cellular computers” to process input signals and perform logic computations.

Orally ingested PCA regulated blood glucose by triggering secretion of insulin or a short variant of human glucagon-like peptide 1 from implanted engineered cells in mouse and nonhuman primate (cynomolgus monkey) models of type 1 and type 2 diabetes. They observed the released insulin or a short variant of human glucagon-like peptide 1 and lowered blood sugar levels when the animals drank concentrated green tea or were given PCA.

The switches offer a highly flexible platform for genetic control, and open new opportunities for gene and cell-based precision medicine the authors said. This biocompatible and versatile food phenolic acid–controlled transgenic device opens opportunities for dynamic interventions in gene- and cell-based precision medicine.

 

 

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