Compact genetic light switches transform disease control

Imagine being able to flip a light switch to control disease pathways inside a living cell. A team of visionary researchers at the Texas A&M University Health Science Center (Texas A&M Health) is making this dream a reality with their groundbreaking genetic tools known as photo-inducible binary interaction tools, or PhoBITs.

Published in Nature Communications, the study describes how PhoBITs enable researchers to harness the precision of a conductor leading an orchestra—using pulses of blue light to command specific proteins to start or stop their activity inside living cells with unparalleled accuracy.

The research demonstrates PhoBITs’ versatility in controlling gene expression, receptor signaling, calcium ion channel activity, cell death and immune responses. In one of the most striking examples, the team engineered a therapeutic “monobody” to selectively bind and inhibit a leukemia-driving fusion protein only when illuminated, leading to suppressed tumor growth.

“The compactness and flexibility of PhoBITs mean they can be tailored for everything from dissecting basic cellular mechanisms to developing clinical-grade, light-guided therapies,” said Yubin Zhou, MD, PhD, FAIMBE, FRSC, senior author of the study and professor at the Texas A&M Health Institute of Biosciences and Technology in Houston.

Because PhoBITs can be activated in targeted tissues or microenvironments—exact neighborhoods of tumor cells—they have the potential to minimize the systemic side effects that limit many conventional treatments. For example, chemotherapy can harm healthy cells in the gut, hair follicles or bone marrow, leading to nausea, hair loss and fatigue. By confining the treatment only to the area it’s needed, PhoBITs open new avenues in cancer therapy, immunotherapy fine-tuning and regenerative medicine.

“Our vision is to integrate these light-controlled switches into next-generation cell and gene therapies, thereby enabling an unprecedented level of control over when and where treatments take effect,” Zhou said.

What are PhoBITs?

At the core of PhoBITs is a surprisingly small system: a seven-amino acid tag called ssrA and its binding partner, sspB. Originally borrowed from bacterial protein machinery, this duo can be engineered to interact or separate depending on exposure to light.

By incorporating light-sensitive domains into sspB, Zhou’s team created two complementary switches:

• PhoBIT1: a light-OFF switch that breaks protein interactions when exposed to blue light.
• PhoBIT2: a light-ON switch that activates interactions in response to blue light.

Because they are so compact, PhoBITs can be inserted into many proteins without disturbing their natural function. In other words, they function almost like universal light switches that can be wired into different circuits, allowing scientists to exert control without disrupting the system.

Applications across biology

To test PhoBITs, the researchers plugged them into some of biology’s most important switches, and the results read almost like flipping breakers in a circuit board.

In gene regulation, PhoBIT1 acted like a dimmer switch for DNA. In the dark, a gene could be silenced; under blue light, its activity flicked back on. This gave researchers the ability to time gene expression with split-second precision.

For cell signaling, PhoBITs turned a normally chemical-driven process into a light-controlled one. By attaching the switch to a type of receptor on the cell’s surface that usually responds to hormones, the team built an “opto-receptor” that could be activated without enzymes, like replacing a lock-and-key system with a motion-sensor light that turns on instantly when you walk by.

With calcium channels, which carry electrical messages in neurons and immune cells, PhoBIT2 worked like a faucet handle. A pulse of blue light opened the tap, letting calcium flow into the cell, and switching off the light closed it again.

Even programmed cell death could be orchestrated. PhoBIT2 enabled researchers to trigger necroptosis, a dramatic pathway where a cell ruptures from within exactly when they wanted. It’s the cellular equivalent of pressing a self-destruct button, a dramatic shutdown triggered only when scientists decide—a level of control that could be valuable for studying how cell death drives conditions like inflammation and neurodegeneration.

Finally, PhoBITs switched on the STING pathway, a molecular alarm system that alerts the body to viruses or cancer. Being able to activate this immune defense with light suggests a future where immunotherapies could be tuned as easily as adjusting the brightness on a phone screen.

A light-guided approach to cancer

The therapeutic potential of PhoBITs came into sharp focus in cancer research. The team engineered a monobody—a synthetic antibody-like protein—that only bound to the leukemia-driving BCR-ABL fusion protein when exposed to light. In animal models, this selective binding suppresses tumor growth, showing for the first time that light could be used to direct a therapy.

This approach highlights how PhoBITs could transform cancer treatment. Instead of flooding the body with drugs that can damage healthy tissue, doctors might one day use light to activate therapies only at the very site of disease.

Looking ahead

Zhou and colleagues envision PhoBITs as part of a new generation of tools for both the lab and the clinic. In research, they offer scientists a way to dissect biological processes with unprecedented control. In medicine, they could be embedded in cell and gene therapies, regenerative medicine and immunotherapy, guiding when and where treatments take effect.

“PhoBITs are more than just research tools,” Zhou said. “They lay the foundation for precision medicine strategies where therapies can be switched on and off with light at will. Our next step is to move these systems toward preclinical and translational models, where light-guided therapies could one day give clinicians unparalleled control over complex diseases in real patients.”

With PhoBITs, biology finally has a master control panel. Each switch governs a different pathway or expression of genes, signals, immunity and even cell death. A pulse of light is all it takes to decide which circuits turn on and which stay off.

By Pooja Chettiar, Texas A&M Health

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