Targeted Cell Control | Stanford News

Thanks to new RNA vaccines, we humans have been able to incredibly quickly protect ourselves from new viruses like SARS-CoV-2, the virus that causes COVID-19. These vaccines insert pieces of temporary genetic material into the body’s cells, which read the code and produce large amounts of specific proteins. In this case, it’s the outer “spikes” of the coronavirus that stimulate the immune system to fight future invaders. .

A new technique for controlling protein production, called RADAR, allows researchers to target exactly the cells they want to make proteins, in contrast to current versions of these techniques, which are introduced into the body without targeting specific cells. can be specified. (Image credit: Getty Images)

The technology is effective and holds promise for all kinds of treatments, says Eerik Kaseniit, a bioengineering PhD student at Stanford University. But at the moment, this kind of his RNA therapy cannot be focused on specific cells. When injected into the body, it indiscriminately makes the encoded protein in every invading cell. If you want to use them to treat only one type of cell, like cells within a cancerous tumor, you’ll need something more precise.

Kaseniit and his advisor, Assistant Professor of Chemical Engineering Gao Xiaojin, I may have found a way to make this possible. They created a new tool called an RNA “sensor”. This is a laboratory-made strand of RNA that reveals its contents only when it enters certain tissues in the body. This method is so accurate that it can home to both cells. type and cell state, It’s only activated if the target cell is making the specific RNA, says Gao.The pair published their findings in the journal on Oct. 5 nature biotechnology.

“For the first time, we can direct protein production only to cells of interest under very specific circumstances,” adds Gao. “Such precision was not possible before.” It may be a fluorescent protein that can be used to track specific cells. Or it could be a protein that triggers cell death and eliminates pathogenic or unwanted cells.

Harnessing the immune system

The new system of pairs, called RADAR, basically consists of two sections. A “sensor” region that latches onto a specific RNA in the body, and a “payload” region that the cell reads and converts into protein. The two sections are separated by a stop codon, a portion of the RNA sequence that renders a chunk of the RADAR’s genetic code inaccessible.

Once the RADAR’s sensor region is successfully latched to the target, the stop codon disappears and the remaining region (its “payload”) suddenly becomes readable. Theoretically, this payload could hold instructions for making any protein in any type of cell at any given time.

This process takes place thanks to a set of existing enzymes called ADARs (adenosine deaminase acting on RNA). It’s a byproduct of the ongoing viral arms race that’s been raging in the human body for thousands of years, Gao says.

Some viruses, such as SARS-CoV-2, influenza, and norovirus, are just protein shells with RNA inside. During replication, these viruses produce very long double-stranded RNA. Viruses can have a devastating effect on the body, so our immune system gradually learns to see these double-stranded RNAs as a threat and quickly shuts down.

“It’s like a red flag. When a cell detects double-stranded RNA, it quickly panics,” says Kaseniit.

But in a strange twist of evolution, our own bodies are Also Makes double-stranded RNA. As viruses have been attacking us, invading our cells, and tinkering with our genetic machinery for thousands of years, some of their genes have been absorbed and incorporated into our DNA. (This is not a fluke; it has happened many times in the past, so the human genome today is Almost 8% are viruses.)

To solve this problem, ADAR evolved as a kind of “test” system. This is how the body decides whether a piece of double-stranded RNA is friend or foe. If we find one created by our own genome, ADAR will edit it slightly to make it less threatening, like removing a few stitches in the middle of a cloth seam, so that the two strands Leave holes or gaps in between. Frying larger fish, the immune system immediately ignores this ragged-looking RNA and continues to fight the real enemy.

RADAR uses that mechanism. When its “sensor” module is latched to a specific target molecule (another piece of RNA), ADAR sees the resulting double-stranded pair as a friendly, harmless variety and faithfully edits it to Make your immune system ignore it. In the process, it erases a small molecular “stop” sign that researchers have incorporated into the middle of her RNA strand. When the RADAR’s payload section is removed, it becomes visible to the cell and the code it contains is converted into a protein.

Potential for new programmable therapies

Kaseniit, Gao, and their collaborators are now testing RADAR in a variety of settings, and the results look promising.Co-authored with Associate Professor of Department of Chemical Engineering Elizabeth Sateley Postdocs Diego Wengier and Will Cody also experimented with plants that do not naturally have an ADAR system, but were able to obtain the same results after adding ADAR enzymes to the mixture. Its versatility and precision provide valuable tools in both research and medicine, and may provide ways for scientists to focus on specific cells in the lab or deliver therapeutics in the body. they say.

“That’s the hope and the dream of RNA as a platform, because you just have to encode the protein you want into a piece of RNA and the cell can make it. Using these regulatory elements, You can specify which target cell to activate on, which is very powerful,” says Kaseniit.