Thanks to new RNA vaccines, we humans have been able to protect ourselves incredibly quickly against new viruses such as SARS-CoV-2, the virus that causes COVID-19. These vaccines deliver a short-lived piece of genetic material into the body’s cells, which then read its code and produce a specific protein — in this case telltale “spikes” that coat the exterior of the coronavirus — preparing the immune system to fight off future invaders.
The technique is effective and holds great promise for all kinds of therapies, says Eerik Kaseniit, Ph.D. student of bioengineering at Stanford. At the moment, however, these types of RNA therapies cannot target specific cells. Once injected into the body, they indiscriminately make the encoded protein in every cell they enter. If you want to use them to treat just one type of cell, such as those in a cancerous tumor, you need something more precise.
Kaseniit and his advisor, assistant professor of chemical engineering Xiaojing Gao, may have found a way to make this happen. They’ve created a new tool called an RNA “sensor” — a strand of lab-made RNA that reveals its contents only when it enters certain tissues in the body. The method is so precise that it can recognize both cell types and cell states, and is only activated when the target cell makes a particular RNA, Gao says. The pair published their findings Oct. 5 in the journal Nature Biotechnology.
“For the first time, you can have only the cells of interest directly produce a protein under very specific conditions,” adds Gao. “That kind of accuracy just wasn’t possible before.” The protein produced can be an antigen – a foreign substance that triggers an immune response – as in the case of vaccines, an enzyme that restores the function of a broken cell, a fluorescent protein that can be used to track specific cells in a research study, or a protein that causes cell death to remove, among other things, pathogenic or otherwise unwanted cells.
Using the immune system
The pair’s new system, called RADAR, is essentially made up of two sections: a “sensor” region that latches onto specific RNAs in the body, and a “payload” region that a cell will read and convert into a protein. . The two sections are separated by a stop codon, an RNA sequence portion that makes part of the RADAR genetic code inaccessible.
If RADAR’s sensor region successfully clicks on its target, the stop codon will disappear, making the remaining region – its “payload” – suddenly readable. In theory, this payload could contain instructions to make any protein, in any type of cell, at any time.
The process happens thanks to an existing set of enzymes called ADAR (Adenosine Deaminases Acting on RNA) — a byproduct of an ongoing viral arms race that has been raging in the human body for millennia, Gao says.
Some viruses, such as SARS-CoV-2, influenza, and norovirus, are just a protein shell with RNA nestled in it. While replicating, these viruses create very long stretches of double-stranded RNA. Since the viruses can have devastating effects on the body, our immune system has gradually learned to see those double-stranded RNAs as a threat and will quickly disable them.
“It’s kind of a danger signal — when a cell sees double-stranded RNA, it immediately scares it,” says Kaseniit.
However, in a strange twist of evolution, our own bodies also make double-stranded RNA. While viruses have attacked us for millennia, burrowed into our cells and played with our genetic machinery, some of their genes have been absorbed and incorporated into our DNA. (That’s no fluke: It’s happened so many times in the past that the human genome today is nearly 8% virus.)
To solve this problem, ADAR evolved as a kind of “test” system – a way for the body to determine whether a piece of double-stranded RNA is friend or foe. If it finds one made by our own genome, ADAR slightly edits it to make it appear less threatening, creating gaps or gaps between the two strands, like removing a few stitches in the middle of a seam of fabric. . The immune system, which has to fry bigger fish, immediately ignores this frayed-looking RNA and continues to fight the real enemy.
RADAR uses that mechanism. When the “sensor” module grabs onto a specific target molecule (another piece of RNA), ADAR sees the resulting double-stranded pair as a friendly, harmless variety and faithfully modifies it so that the immune system will ignore it. In the process, it erases the small molecular “stop” sign that the researchers built into the center of the RNA strand. Once removed, the payload portion of RADAR is visible to the cell and the code it contains is converted into a protein.
Potential for New Programmable Therapies
At the moment, Kaseniit, Gao and their collaborators are still testing RADAR in various environments, but the results look promising. With co-authors, associate professor of chemical engineering Elizabeth Sattely and postdocs Diego Wengier and Will Cody, they even tried it in plants, which don’t naturally have ADAR systems, but after adding ADAR enzymes to the mix, they were able to get the same results. In the future, they say, RADAR’s flexibility and precision could prove a valuable tool in both research and medicine, giving scientists a way to examine specific cells in the lab or deliver therapies into the body.
“That’s the hope and dream of RNA as a platform, because you can just code any protein you want on a piece of RNA and cells will make it. Now with these control elements, we can specify which target cell it will be activated in. That is very powerful,” says Kaseniit.
New RNA-based tool can illuminate brain circuits, edit specific cells
K. Eerik Kaseniit et al, Modular, Programmable RNA Detection Using ADAR Editing in Living Cells, Nature Biotechnology (2022). DOI: 10.1038/s41587-022-01493-x
Quote: Researchers develop new tool for targeted cell control (2022, October 5) Retrieved October 5, 2022 from https://phys.org/news/2022-10-tool-cell.html
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