Summary: Unlocking the secrets of the living brain often requires invasive surgery or expensive, static imaging. However, a breakthrough has successfully translated a revolutionary “blood-to-brain” monitoring platform to primates.
Using Released Markers of Activity (RMAs)—engineered proteins that cross the blood-brain barrier—researchers can now track gene expression and cellular activity in the brain through a simple blood test. This technology allows scientists to watch the “movie” of how neurological diseases like addiction or Huntington’s progress over time in a single individual, providing a level of precision that no current imaging technique can match.
Key Facts
- The Blood-Brain Bridge: RMAs are synthetic proteins designed to escape the brain and enter the bloodstream, carrying real-time data about gene expression from specific neurons.
- Primate Success: The study proved that this technique, originally developed in mice, translates seamlessly to rhesus macaques, a critical final step before potential human use.
- Ultra-High Sensitivity: RMAs can track the activity of as few as tens to hundreds of neurons at a time—far more precise than MRI or PET scans.
- Longitudinal Monitoring: Because it only requires a blood test, the technology allows for “long-term movies” of brain health rather than just “single snapshots” from a biopsy or scan.
- Multiplexed Data: Different markers can be designed to track multiple genes and brain regions simultaneously in one sample using tools like mass spectrometry.
Source: Rice University
Gene therapy has been successfully used to treat a number of diseases, including immune deficiencies, hereditary blindness, hemophilia and, recently, Huntington’s disease, a fatal neurological disorder.
An advance reported in the journal Neuron adds to the technique’s growing track record of evidence supporting the view that it could unlock powerful, personalized therapies: Rice University bioengineer Jerzy Szablowski and collaborators in Vincent Costa’s lab at Emory University found that released markers of activity (RMAs) ⎯ engineered proteins designed to cross the blood-brain barrier and persist in the blood for hours at a time, providing a reliable and noninvasive way to get information about gene expression in the brain ⎯ work just as well in monkeys as they do in mice.
On the route from laboratory discovery to lifesaving treatment, large animal model studies are a critical part of the process. Most research never reaches this stage.
“Our study shows it is fairly easy to translate this noninvasive technique between species,” Szablowski said. “This is exciting because RMAs are an extremely sensitive tool that could be used to track as few as tens to hundreds of neurons at a time ⎯ no existing imaging or monitoring technique can give us that level of precision.”
Alongside precision, RMA technology is also capacious and adaptable: Different serum markers can be designed to track multiple genes across different brain regions.
“Protein detection can be multiplexed,” Szablowski said. “In the future, it should be possible to detect a large number of different synthetic serum markers in a single sample using a variety of biochemical techniques, such as mass-spectrometry or single-molecule protein sequencing.”
Monitoring gene expression in the living, intact brain could reveal critical information about cellular activity, complex cognitive processes and how neurological disease starts and progresses. By retrieving this information using a simple blood test, tracking the same individual brain over time becomes feasible.
“In brain research, longitudinal monitoring is especially important,” Szablowski said, giving addiction as an example.
“Terminal or biopsy readouts are snapshots. By monitoring the same individual over time we can see the downstream effects of gene expression and how they shape future disease or physiology.
“To understand conditions like addiction, you need more than a single snapshot of the brain. We need to see the movie, not just a photograph. Tracking the living brain over time lets us actually watch which genes drive these changes as they happen.”
Szablowski developed the RMA platform based on the observation that antibody therapies failed because antibodies were quick to migrate from the brain into the blood. He zeroed in on the part of antibodies that allows them to cross the blood-brain barrier and used it as a building block for the synthetic reporters.
“It is a short piece of a protein that is responsible for the exit of the protein from the cell into the space between cells, into the extracellular matrix,” Szablowski said. “Simply changing the mouse version of this protein domain for the rhesus macaque version was enough to make the reporter functional in the other species.”
Costa, a co-corresponding author and collaborator on the study, is an associate professor of psychiatry and behavioral sciences at Emory. He and Szablowski started collaborating after Costa read a preprint of the paper in which Szablowski first described the RMA platform and decided he wanted to test it in a large animal model. The two began working together right away, which resulted in the current paper ⎯ a testament to how open science can help research progress faster.
“By removing the bottleneck of complex, repeated brain imaging, this platform completely changes the math for primate neuroscience,” Costa said. “It saves crucial time and resources, allowing us to run the long-term, complex studies needed to bridge the gap between animal models and human treatments.”
Funding: The research was supported by the David and Lucile Packard Foundation (2021-73005) and the National Institutes of Health (R01MH125824, P51OD011132, P51OD011092).
Key Questions Answered:
A: Not quite. It’s more like “reading the health” of the brain. The technology detects which genes are turning on and off in specific neurons. This tells scientists how the brain is physically changing in response to a disease or a drug, which is essential for developing personalized therapies.
A: Transitioning from mice to primates is the biggest hurdle in medical research. Since the “exit signal” that allows the protein to leave the brain is remarkably similar across species, it suggests that this platform is ready to be tested as a tool for human clinical trials soon.
A: Currently, we often only see the damage after a person has passed away or through a grainy MRI. This tool allows doctors to monitor the exact moment a gene starts driving a disease, giving them a window to intervene before permanent damage is done.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neurotech research news
Author: Silvia Cernea Clark
Source: Rice University
Contact: Silvia Cernea Clark – Rice University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Synthetic Serum Markers Enable Noninvasive Monitoring of Gene Expression in Primate Brains” by Sangsin Lee, McKenna Romac, Sho Watanabe, Mykyta Chernov, Honghao Li, Emma Raisley, Kathryn Rothenhoefer, Zachary Dahlquist, Jerzy Szablowski and Vincent Costa. Neuron
DOI:10.1016/j.neuron.2026.01.003
Abstract
Synthetic Serum Markers Enable Noninvasive Monitoring of Gene Expression in Primate Brains
We demonstrate a noninvasive approach for measuring transgene expression in the brains of nonhuman primates using blood-based assays with engineered reporters termed released markers of activity (RMAs).
RMAs cross the blood-brain barrier via reverse transcytosis, allowing detection of brain-derived markers in the bloodstream.
Using this approach, we demonstrate repeated monitoring of multiple transgenes expressed in cortical and subcortical regions over several weeks.
RMAs are sufficiently sensitive to detect circuit-specific, Cre-dependent adeno-associated viral (AAV) expression, and RMA signals are correlated with histological quantification of gene expression in neural tissue.
Together, these findings establish the RMA platform as a cost-efficient and repeatable tool for neuroscience studies in nonhuman primates, enabling sensitive and multiplexed measurement of brain gene expression with a simple blood test.
