New Ribo-Tweezer tool can pluck individual protein pieces out of a working ribosome
Every human cell has millions of ribosomes that make proteins. For decades, biologists thought of ribosomes as tiny, uniform machines. But now a Stanford Medicine team is showing that ribosomes are much more interesting and complicated than previously thought.
Their latest advance is a new tool called the Ribo-Tweezer, which can snatch a single component out of a working ribosome. The technology is opening new avenues of research. For example, by using the Ribo-Tweezer to pluck one protein from the ribosome, the team found a surprise. Apparently, that protein was helping keep stem cells pluripotent—basically, maintaining their "stemness."
"It's such a dense field," said Maria Barna, PhD, an associate professor of genetics. "We're constantly having to invent new technologies to answer new questions." The development of Ribo-Tweezer and the new findings are published in Molecular Cell.
The role of the ribosome
The central dogma of biology is this: DNA is transcribed in the nucleus to make mRNA; the mRNA travels out to a cell's cytoplasm and encounters a ribosome; and the ribosome translates the mRNA into a chain of proteins, which fold up and do the work of the cell.
Ribosomes used to be considered an uninteresting part of this process: consistent mini-machines, just doing their job by rote.
But when Barna was a faculty fellow at the University of California, San Francisco, she learned something about ribosomes. She was studying a mutant mouse whose vertebrae didn't develop properly—for example, the cervical vertebrae in the neck had ribs growing out of them. She was looking for the gene that caused that difference. She assumed her work would bring about new insights into how normal development happens.
When she found the gene, though, she was sure there was some mistake. According to a genetic map, the mouse's mutation was in the gene coding for one of the 80 proteins that make up the ribosome. An undergraduate student dug up a paper from a Japanese research group that had identified the same region of DNA in another mouse with the same developmental change. When she got in touch, she learned that they had dismissed the finding as surprising—but inexplicable. When she told the other researcher that she had found the same thing, he was shocked.
"That's what I love about genetics—it brings you into things you never thought to poke, or ask, or study. But you can't deny the genetic consequences," Barna said.
Since then, biologists' understanding of ribosomes has exploded. Certain genetic diseases have been attributed to mutations in ribosomal proteins. And different types of cells have different types; for example, there are special ribosomes just for the heart—without them, the heart doesn't work properly. In 2023, people from more than 200 research groups attended the first international meeting on ribosomal heterogeneity.
How to pluck a protein
The classic way to find out what a protein does is to knock out the gene that makes it. But that works only if the protein isn't required for survival. Many of the ribosome's 80 main proteins likely play crucial roles in assembling the ribosome inside the nucleus.
Barna wanted to know what those ribosomal proteins are doing after the ribosome moves out to the cytoplasm and gets to work. About seven or eight years ago, her group started discussing how to figure that out, drawing on a blackboard in the lab. "Forget we're biologists," Barna told them. "Say we're playing with Legos or we're playing a kids' game and we have this problem. What can we do?"
The name "Ribo-Tweezer" came along before the technology. "We were like, we're just going to invent a big tweezer to come into the cell's cytoplasm and literally take out individual components of this big machinery—and then we took years to slowly develop the technologies to do that," Barna said.
The Ribo-Tweezer takes advantage of a system known as auxin-inducible degron 2 (AID2). A degron is like a tag or an address label on a protein, telling the cell's garbage system to dispose of it. Biologists use the AID2 system to target and destroy a particular protein.
Barna and her colleagues set their system up with the degron on the protein they wanted the Ribo-Tweezer to remove. They put an auxin receptor on another ribosomal protein, which they chose because it doesn't get added to the ribosome until the ribosome is nearly fully formed and has moved out into the cytoplasm. When they treated the cell with auxin, the tagged protein would be degraded and removed.
"Imagine the ribosome as a large Lego model, built from about 80 protein pieces," said Yuxiang Chen, PhD, a postdoctoral researcher in the Barna lab who co-developed Ribo-Tweezer. "With Ribo-Tweezer, we can pluck out one piece at a time from the ribosome and ask whether it has a special job beyond simply being part of the ribosome."
When Ribo-Tweezers attack
The team decided to start with a ribosomal protein called RACK1 because of its location on the surface of the ribosome. When they used the Ribo-Tweezer system to remove RACK1—originally discovered by Stanford Medicine's Daria Mochly-Rosen in 1991—they confirmed that the removal worked and didn't stress the cell.
Then things got weird. Mouse embryonic stem cells have a characteristic look under the microscope, growing in round clumps. Graduate student Ching Pin Cheng called Barna in to look at the cells without RACK1. They were flat, with long projections. Barna thought, "These are neural stem cells. Something's wrong here."
It took a while for the team to convince themselves, but Barna's initial take turned out to be right: When RACK1 was removed, the mouse embryonic stem cells differentiated into cells with the characteristics of neural stem cells. That implies that RACK1 plays a role in keeping embryonic stem cells in their embryonic state, capable of turning into multiple types of cells. "That was a complete surprise for us," she said.
Moreover, the change was reversible: When the team turned off the Ribo-Tweezer system, the cells went back to their embryonic state.
Barna and her colleagues investigated what else was changing in the cell when RACK1 was removed. They found that removing RACK1 made the ribosome quickly ramp up production of a set of transcription factors. Anshul Kundaje, PhD, an associate professor of genetics and computer science, used machine learning to confirm that those transcription factors were traveling to the nucleus and affecting transcription of genes that are likely to be important for "stemness"—that is, keeping the cell in an embryonic state. That was new; no one knew the ribosome was involved in that process.
The team's observations show what happens when you remove RACK1 from the ribosome—something that wouldn't happen normally. But this means RACK1 must play a critical role in keeping embryonic stem cells in their embryonic state.
Ribo-Tweezer opens new horizons
Cells within a body have the same DNA, but they do different jobs with different proteins. To perform those jobs, they need to regulate which proteins get made. While many biologists have focused on how the cell regulates the earlier step of transcribing genes into mRNA, Barna's team is shining a light on how ribosomes turn mRNA into protein—and how they regulate that process.
The team has also used Ribo-Tweezer to remove other ribosomal proteins from stem cells. They are learning that different ribosomal proteins are responsible for producing distinct sets of proteins—which means that something thought of as a generic machine is actually highly specialized. Barna hopes to eventually deploy the system in nonstem cells to learn more about the role of ribosomes in different cell types.
Eventually, there could be ways to target ribosomes in disease. Mutations in ribosomal proteins can lead to unusual conditions, such as one mutation that causes children to be born without a spleen. Some cancers are also caused by mutations in ribosomal proteins. It might someday be possible to target these mutations with gene-editing techniques, or even with medicines.
"It's so rewarding to be able to look at the new model of gene regulation and what it means for health and disease," Barna said.
Publication details
Yuxiang Chen et al, Ribo-Tweezer: Rapid removal of ribosomal proteins reveals additional layers of post-transcriptional gene regulation, Molecular Cell (2026). DOI: 10.1016/j.molcel.2026.04.023
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Citation: New Ribo-Tweezer tool can pluck individual protein pieces out of a working ribosome (2026, July 28) retrieved 28 July 2026 from https://phys.org/news/2026-07-ribo-tweezer-tool-pluck-individual.html
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