EPISODE 49: Glowing up the Worm Proteome

Welcome to the next episode of the WOrM Podcast 🪱

Today we’re looking at a paper that doesn’t answer a biological question.

Instead, it builds the tools to answer thousands of biological questions in the future.

The ambition?

To fluorescently tag every protein encoded by the C. elegans genome.

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🧬 The big idea

We already have remarkable gene expression atlases based on RNA.

But RNA isn’t the whole story.

Proteins are the molecules that actually perform the work inside cells, and protein abundance often doesn’t match RNA abundance.

The authors argue that the next frontier is a whole-animal protein atlas showing exactly where every protein is found, in every cell, throughout development.

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🔬 How did they test the concept?

Rather than tagging one gene at a time, they asked a much bigger question.

Could they tag three genes simultaneously using CRISPR?

They selected:

• 30 genes
• three different fluorescent proteins
• 10 pooled CRISPR experiments

The approach worked remarkably well.

They successfully generated 24 of the 30 tagged proteins, with all successful tags visible by fluorescence microscopy.

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🌈 Why three colours?

Each fluorescent protein was chosen for a different brightness and wavelength.

The clever part was matching fluorophore brightness to expected protein abundance.

Highly expressed proteins received one fluorophore.

Moderately expressed proteins another.

Low-abundance proteins received the brightest red fluorophore, which also suffers least from worm autofluorescence.

This makes large-scale screening much faster and more practical.

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🧠 The biology was the surprise

Although this is primarily a methods paper, it immediately produced biology.

Several proteins appeared in tissues where RNA datasets suggested they should not be enriched.

Examples included proteins accumulating preferentially in:

• germline
• gonadal sheath
• sperm
• specific neurons
• glial cells

These differences highlight something important.

RNA tells you what might be made.

Protein localisation tells you what is actually there.

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🚀 Why this matters

Around 8% of the C. elegans proteome has already been tagged.

At the current pace, completing the remaining genome could take around 100 years.

Pooling multiple CRISPR edits into single experiments could reduce that dramatically and make a community-wide effort realistic.

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🧠 The bigger picture

Imagine being able to ask:

• Where is every protein expressed?
• Which cells use it?
• Where inside the cell does it go?
• How does localisation change during ageing, stress or disease?

Instead of studying one protein at a time, researchers could explore an entire organism with single-cell resolution.

That’s the long-term vision behind this work.

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🧠 The take-home message

Sometimes the most important papers don’t make a discovery.

They build the infrastructure that allows everyone else to make discoveries.

If the C. elegans community succeeds in creating a complete fluorescent proteome atlas, it would become one of the most valuable biological resources ever generated for any multicellular organism.

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📄 Paper discussed

Eroglu M., Hobert O. (2026)

A pilot study for whole proteome tagging in C. elegans

eLife

DOI: 10.7554/eLife.110717.3

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📩 More info:

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📧 veeren.chauhan@nottingham.ac.uk