Brewing possibilities: Using caffeine to edit gene expression

What if a cup of coffee could help treat cancer? Researchers at the Texas A&M Health Institute of Biosciences and Technology believe it’s possible. By combining caffeine with the use of CRISPR — a gene-editing tool known as clustered regularly interspaced short palindromic repeats — scientists are unlocking new treatments for long term diseases, like cancer and diabetes, using a strategy known as chemogenetics.

Yubin Zhou, professor and director of the Center for Translational Cancer Research at the Institute of Biosciences and Technology, specializes in utilizing groundbreaking tools and technology to study medicine at the cellular, epigenetic and genetic levels. Throughout his career and over 180 publications, he has sought answers to medical questions by using highly advanced tools like CRISPR and chemogenetic control systems.

Chemogenetics refers to the ability to control cellular behavior using externally applied, small molecules — often drugs or dietary compounds — that activate genetically engineered switches inside cells. Unlike traditional drugs that broadly affect many tissues, chemogenetic approaches are designed to act only on cells that have been genetically programmed to respond.

Gene editing with a kick

Zhou’s newest research builds on existing knowledge of genetic “switches” within cells by introducing a new chemogenetic approach that uses CRISPR and caffeine. The process begins  with installing the cells in advance. Genes encoding the nanobody, its matching target protein and the CRISPR machinery are delivered using established gene-transfer methods, allowing cells to produce these components on their own. Once this molecular framework is in place, the process can be externally controlled. When a person later consumes a 20 mg dose of caffeine — such as from coffee, chocolate or a soda — it triggers a nanobody and its matching target protein to bind together, thereby activating CRISPR-driven gene modifications inside cells.

This method also allows scientists to activate T cells, something not possible with other gene-editing methods. T cells serve as the body’s memory bank for past infections, storing blueprints that help fight future threats. Being able to manually activate these cells could give researchers a new way to direct the immune system against specific diseases.

In addition, the team found that certain drugs can reverse the process by causing the proteins to separate, stopping further gene changes and offering even more control over how the system is used, an important feature for safe and reversible chemogenetic therapies. For example, in a therapeutic setting, clinicians could temporarily pause gene-modifying activity to give patients a break from treatment-related stress or side effects, then re-activate the system when conditions are optimal — allowing gene control to be tuned over time rather than left permanently switched on.

“You can also engineer these antibody-like molecules to work with rapamycin-inducible systems, so by adding a different drug like rapamycin, you can achieve the opposite effect,” Zhou said. “For example, if at first proteins A and B are separate, adding caffeine brings them together; conversely, if proteins A and B start out together, adding a drug like rapamycin can cause them to dissociate.”

Rapamycin is a widely available immunosuppressant drug traditionally used as an anti-rejection regiment for organ transplant patients. The drug works by blocking white blood cells from attacking foreign entities in the body. The affordability and availability of the drug make it a prime candidate for applications like this one.

Percolating future possibilities

When an engineered nanobody protein can be switched on by caffeine, it’s called a “caffebody.” By harnessing the power of these caffebodies, Zhou says scientists may someday be able to treat a range of diseases. In the long term, he believes it may be possible to engineer cells that allow people with diabetes to boost insulin production simply by drinking a cup of coffee.

Beyond insulin, the technology can be adapted to control other important molecules, such as those that power T cells. In cancer therapy, for example, caffebodies could be built into T cells to give doctors chemogenetic control over when, where and how strongly the immune system attacks tumors.

In animal model lab studies, Zhou and his team have found that caffeine, as well as its metabolites­ — such as theobromine , which is abundantly available from chocolate or cocoa — could trigger the response and allows for editing with CRISPR. This form of treatment is accessible, easier to control and has fewer side effects than other treatments, he said.

While similar activation techniques have been observed before, this allows for much more control to open and close the circuit. When caffeine is introduced, the team has a few hours — or the metabolization time of caffeine — to control the involved physiological processes or gene editing.  Then, rapamycin can be administered as a stop signal, driving protein dissociation and terminating the process. Few existing approaches offer this level of coordinated start-and-stop control, making the method particularly precise and well suited for both research and therapeutic applications.

“It’s quite modular,” Zhou said. “You can integrate it into CRISPR and chimeric antigen receptor T (CAR-T) cells, and also if you want to induce some therapeutic gene expression like insulin or other things, and this is fully tunable in a very precisely controlled manner.”

Zhou and his team hope to advance the work into further preclinical studies and explore more ways to utilize caffebodies and CRISPR for treating a wide range of medical conditions, bringing everyday molecules one step closer to becoming tools for precision medicine.

“What excites us is the idea of repurposing well-known drugs and even commonly found food ingredients like caffeine to do entirely new tricks,” Zhou said. “Instead of acting as therapies themselves, molecules like caffeine or rapamycin can serve as precise control signals for sophisticated cell and gene therapies. Because these compounds are already well understood, this approach opens a practical path toward translation. Our hope is that one day, clinicians could use simple, familiar inputs to finely tune powerful therapies in a safe and reversible way.”

By Lasha Markham, Texas A&M Health