Brain Gene Expression Measured by Blood Test Works in Primates, Opening a Path to Longitudinal Monitoring
The living brain is one of the least accessible organs in the body for monitoring. Brain biopsies are dangerous and rarely justified outside of tumor diagnosis. Imaging technologies like fMRI and PET scan can show broad patterns of activity but cannot resolve what individual genes are doing in specific neural circuits. This fundamental inaccessibility has slowed progress on understanding how gene expression in the brain drives behavior, disease, and addiction - and it has made personalized therapies that target specific circuits essentially impossible to guide in real time.
A platform developed by Rice University bioengineer Jerzy Szablowski offers a different approach. Reported in the journal Neuron, the latest results show that the system - which uses engineered proteins to carry gene expression information out of the brain and into the bloodstream, where a routine blood test can read it - performs reliably in rhesus macaques. This follows earlier demonstrations in mice and represents a critical step on the road toward potential clinical applications.
How the platform works
The system relies on what Szablowski calls released markers of activity, or RMAs. These are synthetic proteins engineered to be expressed by neurons in response to specific gene activity - essentially, molecular reporters. Once expressed, they are designed to cross the blood-brain barrier, the tightly controlled membrane that normally prevents large molecules from passing from brain tissue into the blood. Once in the bloodstream, the RMAs persist for hours, giving a window of time during which a blood draw can capture the signal.
The key structural element is a protein domain that facilitates the crossing of the blood-brain barrier. Szablowski identified this domain originally by studying why certain antibody therapies failed - they were rapidly exiting the brain into the blood, which was the problem he needed to solve in reverse. For the RMA platform, that same exit mechanism becomes the feature. "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," he said.
Why the primate result matters
Most biomedical research never advances beyond mouse studies. The biochemistry, anatomy, and physiology that determines whether a molecular tool will function in a human-sized brain are substantially different from what governs mouse outcomes. Large animal validation - typically in non-human primates - is widely considered a necessary gateway before human studies can realistically be contemplated. The RMA platform now clears that hurdle.
"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."
The sensitivity is notable. Current non-invasive brain monitoring techniques - fMRI, EEG, PET - integrate activity across large populations of neurons. The ability to track gene expression in small defined circuits could, in principle, give researchers and eventually clinicians a view of brain function at a resolution that has never been available without putting electrodes or biopsies into brain tissue.
Longitudinal monitoring and the addiction example
Vincent Costa, an associate professor of psychiatry at Emory and co-corresponding author, emphasizes what continuous monitoring over time makes possible. "By removing the bottleneck of complex, repeated brain imaging, this platform completely changes the math for primate neuroscience. 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."
Szablowski uses addiction as an illustration of why a longitudinal view matters. A brain biopsy or a single imaging session captures a moment. Addiction - like many neurological conditions - is defined by changes that unfold over months and years, driven by shifts in how genes are expressed across repeated experiences. "We need to see the movie, not just a photograph," he said. Tracking the same individual brain over time, through sequential blood draws, would allow researchers to watch those changes as they happen.
The platform also allows multiplexing: different RMA sequences can be designed to report on different genes simultaneously, with distinct protein sequences that can be distinguished in a single blood sample using mass spectrometry or single-molecule protein sequencing. This means multiple circuits could be monitored in parallel rather than sequentially.
Current limitations are real. The platform requires delivering the RMA genetic constructs into specific brain regions, likely via viral vectors, before any monitoring can begin. That delivery step involves its own safety and targeting challenges, and the viral approaches used in research settings would need to be refined substantially for clinical use. The Emory-Rice collaboration began when Costa read Szablowski's preprint and reached out directly - a detail the authors note as evidence of how open science can accelerate progress.