HMN 2025: What is the molecular ‘reset button’ for reading the brain through a blood test

Tracking how genes switch on and off in the brain is essential for understanding many neurological diseases, yet the tools to monitor this activity are often invasive or unable to capture subtler changes over time. One emerging alternative is to use engineered serum markers—small proteins produced by targeted brain cells that can travel into the bloodstream, where they can be measured with a simple blood test.

Referred to as released markers of activity, or RMAs, these molecules can serve as a sensitive tool for monitoring brain activity, but they also persist in the bloodstream for many hours. That long half-life can drown out intervening changes in the biological signal of interest.

Developing erasable markers

Rice University bioengineers have developed a way to make RMAs even more sensitive, pointing to other diagnostic scenarios where they could be deployed.

According to a study published in Proceedings of the National Academy of Sciences, the team designed an erasable marker that can be cut apart inside the bloodstream by an enzyme which acts like a pair of molecular scissors: Once it cleaves the RMAs, the previous signal disappears and a new reading becomes possible.

“The key advance here is a new way of thinking about serum markers—that we can modify them inside the bloodstream when we need to,” said Jerzy Szablowski, assistant professor of bioengineering at Rice and a corresponding author on the study.

“This broad concept has many potential applications, ranging from extending the marker’s half-life to improve detectability, or erasing them to remove the background signal and improve temporal resolution. Currently, markers are usually extracted from the body and interpreted ‘as-is,’ which limits their usefulness.”

In an animal model, a single injection of the cleaving enzyme removed about 90% of the RMAs’ background signal within half an hour. That reset made it possible to observe subtle gene-expression changes that had previously remained undetected.

The researchers also showed they could repeat this process and measure how quickly the marker reappeared, offering a clearer picture of how gene activity evolves over time.

Potential clinical and research applications

This approach could eventually enable clinicians to detect problems or measure any changes in how a patient responds to treatment with greater precision, using simple, minimally-invasive testing.

“We introduced a modification where the RMAs were made sensitive to a targeted protease—an enzyme that can cleave them in half,” said Shirin Nouraein, a graduate student in Rice’s Systems, Synthetic and Physical Biology program who is a first author on the study.

“Using this enzyme, we separated the domain that provides signal from the domain that makes it last a long time in blood, making the background signal decay within minutes. We found a significant elevation in signal changes when we used these markers to track the dynamics of gene expression in the brain.”

The approach could have an impact on areas of medicine beyond neurology: If markers can be edited inside the body, their behavior can be tuned for many diagnostic purposes, including, for example, using RMAs for detecting tumors or lung disease using urine tests.

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