Scientists use blood tests to track gene expression in the brain

The brain is the body’s most protected organ, enveloped in a complex and almost impenetrable barrier of specialized blood vessels. Although this particular anatomical configuration 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 diseases.

According to a study published in Natural biotechnology.

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

“Typically, if you wanted to look at gene expression in the brain, you had to wait to do a postmortem analysis,” said Szablowski, an assistant professor of bioengineering at Rice’s George R. Brown School of Engineering. . “There are more modern neuroimaging techniques that can do this, but they lack the sensitivity and specificity to track changes in specific cell types.

“Using the RMA platform, we can introduce a synthetic gene expression reporter into the brain, which produces a protein capable of crossing the blood-brain barrier. We can then measure changes in expression of a gene of interest with a simple blood test.”

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

“Every time these injections were given, the antibodies simply disappeared – they didn’t stay in the brain long enough for effective therapy,” he explained. “But we thought the failure of antibody therapies could be repurposed to our advantage. What if we took the part of the antibody responsible for this leak and attached it to a protein that could be easily detected? Then we could see where, when and how a large part of a particular gene was expressed in the brain.”

Other researchers had previously determined 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 his team attached the part of the antibody that helps it cross the blood-brain barrier to a common reporter protein to take advantage of this biological escape hatch. When the group then connected the RMAs to a specific gene and expressed that gene in a mouse’s brain, they could see that expression reflected in the animal’s blood.

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

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

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