A conversation with Andrea Ablasser, laureate of the 2024 Liliane Bettencourt Prize for Life Sciences.
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The cGAS–STING pathway senses and regulates the cellular response towards microbial and host-derived DNAs.Credit: byakkaya/ Getty Images
Andrea Ablasser, an immunologist and laboratory head at the Swiss Federal Institute of Technology Lausanne in Switzerland, leads a team that aims to understand how immune system cells detect pathogens, and the fundamental mechanisms that provide host defence. This year, Ablasser has been awarded the Liliane Bettencourt Prize for Life Sciences for her innovative work in revealing how cells sense and react to DNA in the innate immune response.
What got you interested in innate immunity? 
Andrea Ablasser is the winner of the 2024 Liliane Bettencourt Prize for Life Sciences.Credit: Romain Redler – Art in Research for Fondation Bettencourt Schueller
I began my career studying medicine and developed a deep interest in understanding the mechanisms of how our body functions and malfunctions. I was initially drawn to cancer research and became fascinated by the potential of using the immune system to combat the disease. By chance, I began working in a lab that studied the molecular mechanisms of cancer immunity. This helped me realise that cancer immunotherapy was largely observation-driven with limited mechanistic understanding. So, I went more into the molecular mechanisms of how innate immunity is shaped, which led me to the role of nucleic acid.
How did you come to study the DNA-sensing pathway?
When I started working on nucleic-acid-induced immunity, there was a general concept known as pattern recognition. This is the idea that microbial infection releases pathogen-specific molecular features that can be recognized, allowing the innate immune system to discriminate self from non-self. But it became increasingly clear that there was also a mechanism driving recognition of microbial DNA within the cytosol (cellular fluid outside the nucleus), and that this mechanism was unknown. So, we started tackling this problem.At the time, it was not clear that this mechanism had such an outstandingly important biological role. Within the last decade, however, we have discovered its surprising importance in shaping distinct pathological conditions, especially as we now know it also recognizes self DNA released by stressed or damaged cells.
Tell us about this pathway. What did you discover?
The cGAS-STING pathway begins with an enzyme called cGAS-sensing double-stranded DNA present in the cytosol. It triggers a molecular messenger called cGAMP, which activates a protein called STING. This stimulates the cell to produce molecular signals called type 1 interferons, which coordinate the inflammatory response. We’ve explored several parts of this pathway. For example, we described cGAMP, noting that it has unique immunostimulatory properties, which is now being used in the clinic.
We, along with other labs, have uncovered even more features of this pathway and showcased its importance for antiviral and antimicrobial immunity. It is now becoming increasingly evident that it is also key for triggering inflammatory diseases, during neurodegeneration and ageing.
Microglia cell’s mitochondria with their DNA. Andrea Ablasser and colleagues discovered that cytosolic DNA released from perturbed mitochondria defines a mechanism by which cGAS–STING signalling is engaged in the ageing brain.Credit: Andrea Ablasser Lab/EPFL
cGAS can also recognize self DNA, released when cells are damaged, not just by microbial infection but also if there’s a loss of homeostasis, like in cancer or autoimmunity.
Below a certain threshold, our cells can probably tolerate self DNA, but if they build up through a pathological process, excess can stimulate this inflammatory reaction. This response towards loss of homeostasis is often driving the disease symptoms. In viral infections, this can lead to an exaggerated immune response. We’ve shown that if you target the cGAS-STING pathway in mouse models of COVID-19, it can reduce the disease severity.
One idea now is to interfere with these maladaptive inflammatory states, and we’ve worked on a compound targeting STING that is now being developed for the clinic. It is early days, but it seems like a very promising approach to devise an entirely novel anti -inflammatory therapy.
Do we need new anti-inflammatory medicines?
Targeting specific inflammatory pathways, rather than using treatments like glucocorticoids, which suppress many mechanisms, will leave other signalling systems intact, reducing immunosuppression. The goal isn’t to completely block inflammation, but to lower its threshold for therapeutic benefit. This approach is similar to anti-cytokine therapies, where blocking one cytokine affects others but remains safer as other cytokines still function during acute inflammation. So, targeting innate immune pathways selectively in a similar fashion could be safer.
What will you do next?
I’ve often questioned whether to continue working on the cGAS-STING pathway, as it gets more specific and as the field explodes. But I recognize the importance of deeply understanding this pathway. We typically study it in isolation, but it interacts with many other pathways, and our knowledge of these interactions is limited. We need a holistic approach to better integrate our knowledge of innate immune pathways. Fundamentally, we aim to understand the regulatory mechanisms of cGAS-STING. We’ve identified a few, but a precise molecular and structural understanding is crucial for modulating them safely. Long-term, I want to develop new inhibitors and activators, and explore the evolutionary aspects of this pathway, which is fascinatingly old.
What does the prize mean for you?
I’m very humbled and it’s a huge recognition of my lab’s work. It’s also a great honour to look back on past awardees and I’m very proud of being selected amongst this crew. It is also a great motivation to aspire to new discoveries in the innate immunity field.
For more information on the Liliane Bettencourt Prize for Life Sciences and previous laureates, visit the website
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