Revolutionary blood test monitors the dynamics of gene expression in the brain

The brain is the body’s most protected organ, covered in a complex and nearly impenetrable barrier of specialized blood vessels. While this particular anatomical arrangement protects it from outside invaders, it also makes it difficult for researchers to study how specific genes are expressed ⎯ and how such changes in gene expression can lead to disease.

Now Rice University scientists have developed a non-invasive way to monitor the dynamics of gene expression in the brain, making it easier to investigate brain development, cognitive function and neurological diseases, according to a study published in Biotechnology of nature.

Rice industrialist Jerzy Szablowski and his colleagues have engineered a unique class of molecules, known as released activity markers (RMAs), that can be used to measure gene expression in the brain through a simple blood test.

Usually, if you want to look at gene expression in the brain, you’d have to wait to do a postmortem analysis. There are some more modern neuroimaging techniques that can do this, but they lack the sensitivity and specificity to track changes in specific cell types.

With the RMA platform, we can introduce a synthetic gene expression reporter into the brain, which produces a protein that can pass through the blood-brain barrier. We can then measure changes in expression for a gene of interest with a simple blood test.”

Jerzy Szablowski, assistant professor of bioengineering at Rice’s George R. Brown School of Engineering

Szablowski first considered the possibility of a synthetic gene expression reporter after noting that the brain would quickly clear injections of antibody therapy.

“Whenever these injections were given, the antibodies would just disappear ⎯ they wouldn’t hang around in the brain long enough for an effective treatment,” he explained. “But we thought that the failure of antibody therapies could be repurposed to our advantage. What if we took the part of the antibody responsible for this escape and attached it to a protein that could be easily detected? Then we could see where, when and how much of a particular gene was expressed in the brain.”

Other researchers had already found that antibodies cross the blood-brain barrier using the crystallizable neonatal fragment receptor (FcRn), a gene known to help maintain the level of antibodies present throughout the body. Using sophisticated bioengineering techniques, Szablowski and team attached the part of the antibody that helps it cross the blood-brain barrier to a common reporter protein to exploit this biological escape hatch. When the team attached RMAs to a specific gene and expressed that gene in the brain of a mouse, they were able to see that expression reflected in the animal’s blood.

“This method is very sensitive and can track changes in specific cells,” Szablowski said. “The production of this protein in about 1% of the brain increased its blood levels up to 100,000 times compared to baseline. We could specifically monitor the expression of this protein with just a blood test.”

For now, Szablowski sees RMAs as a vital research tool to help scientists better monitor gene expression in the brain. For example, he said, the RMA platform could be used to examine how long new gene therapies remain in the brain over time.

“We could monitor these new treatments with just a blood test and continue to monitor them over time because the RMA platform is non-invasive,” he said. “But we can also use RMA to study disease-related gene expression. Being able to track different gene expression changes will allow us to understand what leads to disease and how the disease itself changes gene expression in the brain. This could provide new clues to drug development or even how to prevent neurological diseases in the first place.”

The David and Lucile Packard Foundation (2021-73005) and the National Institutes of Health (R21EB033059, DP2GM140923, R00DA043609, F31NS125927) supported the research.