Gene Switch Uses Electromagnetic Fields to Control Genes Remotely

Researchers say gene switches currently offer limited temporal and spatial precision and can also have adverse effects. Now, a recent study, “Electromagnetic field-inducible in vivo gene switch for remote spatiotemporal control of gene expression” in Cell, describes an electromagnetic field-inducible gene switch that enables fully reversible, safe, and precise control over gene expression.

The scientific team from Dongguk University in South Korea believes this represents a powerful non-invasive tool for understanding gene expression and for gene therapy.

DNA contains regulatory elements that control when, where, and to what extent specific genes are turned on or off. They can be co-opted to create “gene switches” that hold significant potential for understanding gene expression and for therapeutic applications, particularly for the non-invasive treatment or management of genetic disorders.

In recent years, researchers have developed several gene switches that enable the remote control of gene expression in living organisms using stimuli such as drugs, light, heat, ultrasound, and electrical signals. However, current versions are limited in offering precise control over the timing and duration of gene expression, according to the Dongguk University investigators. Additionally, drug-based gene switches can have undesirable adverse effects, while some stimuli, such as light, can make penetrating deeper tissues challenging.

Addressing these limitations, Jongpil Kim, PhD, and doctoral student Yerim Hwang from the Institute for Stem Cells and Regenerative Medicine at Dongguk led a group that developed a novel electromagnetic field (EMF)-responsive gene switch.

“In previous studies, extremely low frequency EMF fields have been shown to modulate expression of specific genes involved in stress response, epigenetic remodeling, and cellular signaling pathways. Moreover, EMF is non-invasive, fully reversible, and can precisely penetrate target tissues or areas of the body, making it highly attractive for remote control of gene switches,” explained Kim. “In this study, we utilized the promoter of the Lgr4 gene to create a robust EMF-inducible gene switch and demonstrated its applications in Alzheimer’s disease (AD) modeling and reversing aging markers in mice.”

To identify EMF-responsive genes, the researchers performed single-cell RNA sequencing (scRNA-seq) on mouse brain tissue following exposure to an EMF of 2.0 millitesla at 60 hertz. The team found exclusive upregulation of Lgr4 expression. Through a series of validation experiments, the team found that the promoter of Lgr4 was well suited for constructing an EMF-inducible (Ei) gene switch, exhibiting precise activation with no detectable adverse effects during the study.

To evaluate the system in living animals, the researchers linked the Ei element to a reporter that produces green fluorescent protein (GFP), allowing gene activity to be visualized. They then generated transgenic mice carrying this reporter. Following EMF exposure, the mice showed strong GFP expression throughout the body, while targeted EMF exposure produced localized gene expression in specific organs.

When EMF stimulation was discontinued, gene expression returned to baseline within 24 hours, demonstrating that the Ei gene switch is highly tunable, reversible, and capable of precise remote control of gene expression.

Using a genome-wide CRISPR-Cas9 knockout screen, the researchers identified cytochrome b5 type B (Cyb5b), a membrane-associated protein, as the biological sensor for EMF. “This may be the first reported molecular sensor for electromagnetic fields,” noted Kim. Further tests revealed that due to EMF exposure, Cyb5b produces rhythmic calcium influx oscillations in cells, functioning as a specific code for activating the target gene.

The researchers also demonstrated several applications of the Ei gene switch, e.g., they established an AD mouse model that decouples brain aging from amyloid β plaque deposition. In addition, cyclic EMF exposure was used to achieve partial cellular reprogramming in aged and progeroid mice, improving several aging-associated markers without detectable adverse effects. The team also restored serotonin levels and reduced depression-like behaviors in mice by controlling expression of the Tph2 gene.

“This technology could move gene therapy away from a single, irreversible dose and toward simpler, real-time treatments administered by physicians or even wearable devices,” said Hwang.

Although further validation and testing are required, the Ei gene switch represents a promising platform for developing non-invasive, remotely controlled gene therapies, she added.