Department of Informatics

Finding new mysteries in our tiniest parts

There is still a lot we don’t know about cells. This lab has made a discovery that challenges previous understanding of cellular structures.

Sushma and Jack sitting in Høyteknologisenteret.
Microscope image by Thomas Stevenson, portrait by Randi H Eilertsen. UiB.

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Biomolecular condensates are groups of molecules that form small droplets within cells. Scientists have identified hundreds of different types of these condensates, each with its own unique properties and functions.

At the Computational Biology Unit at UiB, the Grellscheid Group and their collaborators have just published an article in Science Advances describing a new method for analysing biomolecular condensate droplets, specifically stress granules.

“Stress granules are a type of condensate that forms in response to cellular stress and may play a role in protecting cells from damage,” explains Professor Sushma Grellscheid. She has a background in molecular biology and is now leading a group of computational and life scientists. Together they’re working to understand how our bodies function on the most basic levels.

“Condensates are fascinating structures. They are easily observed in most cell types, but due to their droplet nature, are notoriously hard to study in their native state,” says Sushma Grellscheid.

“Hopefully our method can be applied to other types of condensates as well.”

A mysterious layer

The big discovery was made when the team was trying to study the droplets in their natural state.

Scientists have not yet figured out what these droplets are doing inside our cells. Some believe they have a function related to our genes; some believe they don’t have a function at all.

The Grellscheid group were interested in whether the condensates behave like simple liquid droplets, and if so, what their liquid properties would be.

They decided to focus on measuring the interfacial tension. Interfacial tension can tell us a lot about how a material interacts with its surroundings. Taking examples from everyday experience, it determines whether a drop of water will sit on a surface or spread out across it, and it is a key factor that influences how quickly two drops merge.

However, measuring surface tension in biomolecular condensates is not an easy task. The droplets are very small and cannot be observed intact outside of living cells. There were existing models used to study surface tension in other types of droplets, but these were often too simple and inaccurate.

To overcome these challenges, the researchers used a protein that they knew would enter stress granules, which had a fluorescent tag that allowed them to see the droplets under a microscope. By observing the droplets in live cells, the researchers were able to use a computer programme to measure the natural vibrations of the droplet's surface.

They found that the surface of stress granule droplets vibrated in a unique way, different from that of normal liquids. The researchers used this information to create a spectrum of vibrations for the droplets and compared it to what they would expect to see from a droplet of a normal liquid.

The droplets are known to not have a membrane, and yet the measurement data only fits if you include bending rigidity as a parameter. In layman’s terms, this implies the droplets may not be simple liquids after all: Even though there is no membrane, everything points to there being something special covering the structure.

Droplets glowing under microscope

An added protein causes the droplets to light up under the microscope, allowing the scientists to see the droplets.

Thomas Stevenson, UiB

More than just stress granules

By measuring surface tension and other properties of these droplets, scientists can gain insights into how they interact with other molecules within cells and how they may contribute to cellular processes.

“What makes this study special is that we had biologists, physicists and computational scientists all working together on the same problem,” states Jack Law, a PhD student who has been working on the project. “I’ve really enjoyed this interdisciplinary way of working,” he says, and points out the international aspect. “Our collaborator, Professor Halim Kusumaatmaja at Durham University, has been super helpful.”

The researchers hope that by understanding the interfacial tension and other properties of biological condensates, scientists all over the world will be able to make even more discoveries about their unique properties and functions. To tackle condensate related diseases there needs to be a way to accurately measure the characteristic ‘fingerprint’ of a healthy liquid condensate versus one tending towards pathological hardening.

“Finding something unexpected like this bending rigidity is always very exciting. It opens up so many new questions. For example, do all condensates have a bending rigidity? What is causing it? What other properties can we measure, and are there any more surprises in store?" Grellscheid  questions.  "Hopefully, we and other scientists in the field can start tackling these question in the next few years."