Watching proteins move to guide drug discovery
A technology developed at QBI reveals the movements of individual molecules inside living brain cells.
Why does this matter?
The nanoscale world in which proteins operate is highly chaotic and membrane proteins very often move randomly or huddle together in tiny nanoclusters. For QBI researchers Professor Frederic Meunier and Dr Tristan Wallis, watching this activity inside living cells revealed something a still image could not: the clusters were highly dynamic.
“Clustering wasn’t a surprise. The fact that it’s transient was a surprise."
These fleeting interactions matter because proteins need to be in the right place at the right time to function effectively. Tracking their movements at the nanoscale can help scientists understand both healthy cell activity and what happens when those processes break down.
The team uses a technology platform called NASTIC (Nanoscale Spatiotemporal Indexing Clustering) to study movement at the level of individual molecules in living cells. Combining super-resolution microscopy with this advanced analysis reveals how proteins move and gather inside living brain cells, and how potential drug candidates influence that behaviour.
The technology is now being commercialised through Brisbane-based startup Accretion Bio, which is initially focused on neurodegenerative diseases including Alzheimer’s and Parkinson’s.
Adding time to the picture
Super-resolution microscopy allows researchers to track individual molecules beyond the limits of conventional light microscopy. But the resulting data can be difficult to interpret.
“Within what looks like noise are the paths of proteins moving through cellular compartments"
“NASTIC analyses those tracks to reveal where proteins gather and how those gatherings change over time. We wanted to see molecules moving in real time, not just capture a snapshot.”
Adding a time dimension changes the questions researchers can ask. Tracking proteins’ movements can reveal when and how they form clusters and how long they last.
The time element changes the questions researchers can ask. A concentration of proteins in one image might look much like a concentration in another. Following the molecules shows whether they stay together or arrive briefly before moving on.
When proteins become trapped
The ability to follow those nanoscale movements is especially valuable when examining proteins that are mutated in disease.
In studies involving disease-linked mutations, Professor Meunier has observed proteins becoming trapped within very long-lasting clusters.
“NASTIC allows us to track how key proteins move, cluster and interact inside living neurons and to find out how potential drug candidates influence those behaviours."
“By comparing healthy and disease-associated patterns, we can introduce drug candidates and see whether protein behaviour shifts towards a healthier state.”
The aim is to help drug developers understand what a compound actually does to its target inside a living cell. That information could help them decide which candidates warrant further investigation early in discovery.
Following a scientific question
The NASTIC platform draws on almost two decades of QBI research led by Professor Meunier’s laboratory.
Questions about why molecules paused in particular locations eventually led to collaborations with biophysicists and mathematicians to better understand the nanoscale world inside our cells.Dr Wallis said his coding experience also played a key role in shaping the technology.
“During the COVID pandemic, I revisited gaming algorithms and found they could also be used to track molecules in space and time."
The researchers later began exploring how the technology could be applied beyond their own laboratory.
A new class of evidence
With support from UQ’s commercialisation company UniQuest, NASTIC has been spun out into startup Accretion Bio, backed by global venture firm Antler.
Accretion Bio CEO Phillip Craig said the company is already engaging with pharmaceutical and biotechnology partners while advancing its own neurodegenerative disease drug discovery program.
“The industry has been making high-stakes decisions without a crucial layer of data about what’s happening inside a living cell.”
“NASTIC allows us to assess how a drug candidate changes its target’s behaviour in real time, early in discovery. That is not an incremental improvement, it is a brand-new class of evidence.”
The platform could also have applications in immunology and cancer research, where protein clustering also influences cellular responses.
For the Accretion Bio team, commercialisation offers a pathway to translate fundamental research into better-informed decisions about future medicines.
“Progressing the platform from discovery to commercial applications is an opportunity to help researchers and drug developers make better-informed decisions and, ultimately, improve outcomes for patients affected by neurodegenerative diseases."
Read the UQ media release here.
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