How ribosomes proved their worth

In the past, biologists viewed ribosomes as a passive machine — feed it a strand of genetic material and it will assemble the corresponding protein. “I’ll be the first to admit that for a long time I thought ribosomes were themselves not going to be interesting for controlling key facets of cell and tissue biology,” Barna said.

Then, work by Barna and others beginning in the early 2000s showed that changes in ribosome genes led to unusual developmental defects and diseases. Barna’s own discoveries helped push the field forward, showing that ribosomes might be selective, even strategic, about which proteins they produce.

“We used to think there was just one kind of ribosome,“ she said. “Now, it looks like there could be millions of variations, each with different roles in different cells, and layers upon layers of regulation that let ribosomes play an active role in regulating cells."

How ribosomes are linked to disease

Changes to how ribosomes work can have drastic implications for human health. A few examples:

• Babies born with mutations in ribosome genes often have severe disease — some are missing entire organs or have bone malformations; others have serious forms of anemia.
• Conditions like Alzheimer’s and Parkinson’s are linked to clumps of misfolded proteins, which can result from faulty ribosome activity.
• Cancer cells often have hyperactive ribosomes to produce the proteins that tumors need for rapid growth.

New methods of studying ribosomes

Ribosomes are so tiny — and so plentiful in cells — that pinpointing the precise patterns in which they cluster has been difficult with standard microscopy. Barna’s team — led by former graduate students Zijian Zhang, PhD, and Adele Xu, MD, PhD — developed two cutting-edge techniques to study ribosomes at an unprecedented level of detail:

• RiboExM (ribosome expansion microscopy): With this technique, scientists embed cells in a special gel and expand them, making it possible to zoom in on ribosomes and see how they are arranged in much finer detail.
• ALIBi (optogenetic proximity labeling): Using light to activate molecular tags in specific, small areas of the cell, researchers can isolate and study ribosomes based on their location. This reveals what proteins are attached to them and what genetic messages they are reading.

“Previously we could see ribosomes as these black dots all over a cell but couldn’t really differentiate them,” Barna explained, “or see how any of them associated with each other or with structures in a cell.”

What the methods showed

Using the techniques in tandem, Barna and her colleagues discovered that ribosomes with a unique makeup form specialized clusters to produce proteins near where they are needed. For instance, proteins needed for energy production by mitochondria — the cell’s powerhouses — are produced by clusters of ribosomes located very close to mitochondria. 

“This really leads to a whole new way of thinking about where proteins are made, and how,” Barna said.

They also showed, for the first time, how ribosomes are arranged in neurons — research that could eventually be key to understanding what goes wrong in ribosomes during neurodegenerative diseases.

Why this could be a game-changer

Until now, scientists have had only rough, ground-level surveys of ribosome activity — like trying to map a forest while standing in the middle of it. These new techniques are like launching high-resolution satellites, allowing researchers to see the entire landscape of protein production in cells with remarkable clarity.

The initial data collected with RiboExM and ALIBi support the growing evidence that ribosomes are not all created equal — their composition can vary between cell types and even within a single cell, affecting which proteins get made when and where.

Mapping ribosomes at this fine level could change how we understand and treat many diseases. By pinpointing where and how ribosomes operate — and malfunction — researchers can start developing therapies targeting subsets of ribosomes without disrupting protein production across the entire body.

Up next for ribosome study

Barna’s lab plans to further refine their tools to capture ribosome activity in even more detail and in more diverse cell types.

They hope to investigate how ribosome composition and clusters change in response to various diseases and environmental conditions. Barna also hopes to understand how ribosome composition and activity change with aging — a time when protein production becomes more error-prone and less efficient.

Barna says other researchers have already asked about using RiboExM and ALIBi themselves, and she hopes the methods continue to gain traction.

“This sets a new bar for the level of detail and resolution that should be expected when studying the ribosomes from now on,” she said.

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