Rice University bioengineers have developed a new method to improve the sensitivity of released markers of activity (RMAs), which are small proteins produced by targeted brain cells that can be measured in the bloodstream. This advancement could enhance the ability to monitor gene activity in the brain and other organs with greater precision.
The research, published in Proceedings of the National Academy of Sciences, describes an erasable marker system. The team engineered RMAs so they can be cleaved inside the bloodstream by a specific enzyme. When this enzyme is introduced, it cuts apart the RMAs, effectively erasing previous signals and allowing for a new measurement.
"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 animal tests, researchers found that injecting the cleaving enzyme removed about 90% of background RMA signals within half an hour. This reset allowed detection of subtle changes in gene expression that were previously hidden. The process could also be repeated to measure how quickly markers reappear, providing more detailed information on gene activity over time.
"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 researchers suggest this approach may have broader medical applications beyond neurology. By editing markers inside the body, their properties could be adjusted for various diagnostic purposes such as detecting tumors or lung disease through urine tests.
This project reflects Rice University's focus on brain research and aligns with its recently established Brain Institute’s mission to develop technologies for understanding and treating brain disorders.
Funding for this research was provided by grants from both the National Institutes of Health and National Science Foundation. The authors note that their findings represent their own work and not necessarily those of their funding organizations.
