The physicist-turned-biologist who revolutionized our understanding of immune cell activation using super-resolution microscopy
Imagine trying to solve a complex mystery while wearing foggy glasses. For decades, this was the challenge facing immunologists trying to understand how our body's defense cells spring into action. In 2011, Professor Katharina Gaus and her team at the University of New South Wales permanently cleared the lens, using super-resolution microscopy to witness molecular processes inside living immune cells for the first time. Their discovery overturned established scientific doctrine and revealed the precise molecular "switch" that activates our immune response—a breakthrough with far-reaching implications for treating conditions from autoimmune diseases to cancer 1 4 6 .
Gaus, who passed away in 2021, left an extraordinary legacy that extended beyond her groundbreaking research. As a physicist turned cell biologist, she embodied interdisciplinary science, establishing world-class research facilities and mentoring the next generation of scientists.
This article explores how her unique blend of physical and biological sciences produced insights that continue to shape our understanding of the immune system today.
To appreciate Gaus's contribution, we must first understand the players in this cellular drama. T-cells are critical frontline soldiers in our immune system, constantly patrolling our bloodstream for signs of invaders like viruses, bacteria, or cancer cells. For decades, scientists understood that these cells must somehow recognize threats and trigger a massive immune response, but the exact mechanism remained elusive.
The prevailing theory suggested that T-cell signaling began at the cell surface with molecular clusters forming around activated receptors. Like soldiers gathering around a commander receiving vital intelligence, these clusters were thought to initiate the immune response.
This understanding was based on conventional microscopy techniques, which offered limited resolution—much like trying to observe a conversation in a crowded stadium from the highest bleacher 1 .
Gaus approached this biological question with a physicist's mindset, questioning whether the tools available were adequate to answer fundamental questions about cellular processes. Her skepticism about existing models and determination to develop better observational methods would lead her to rewrite the textbook on immune activation.
The diagram below illustrates the traditional understanding of T-cell activation versus Gaus's discovery:
Gaus's breakthrough was made possible by her work with super-resolution fluorescence microscopy, a technology that earned the Nobel Prize in Chemistry in 2014. At the time of her discovery, only half a dozen of these "super" microscopes existed worldwide, with Australia's only located in her facility 1 .
Instead of illuminating all target molecules simultaneously, this technique makes them light up one at a time
Each molecule's position is recorded with nanometer precision while neighbors remain dark
Thousands of individual localizations combine to create a "super-resolution" image
"In conventional microscopy, all the target molecules are lit up at once and individual molecules become lost amongst their neighbours—it's like trying to follow a conversation in a crowd where everyone is talking at once. With our microscope we can make the target molecules light up one at a time and precisely determine their location while their neighbours remain dark"
This technology allowed Gaus's team to see details as small as 10 nanometers—a resolution that revealed cellular structures previously invisible to scientists.
| Microscopy Type | Resolution |
|---|---|
| Conventional Light Microscopy | ~200 nm |
| Super-Resolution Microscopy | ~10 nm |
Super-resolution microscopy provides 20x better resolution than conventional light microscopy.
Gaus and her team focused on studying a specific protein important in early immune response. Using Australia's only super-resolution microscope, they imaged this protein molecule-by-molecule within living T-cells, revealing something astonishing that overturned decades of scientific understanding 1 .
The team prepared live T-cells with fluorescent tags attached to key signaling proteins, allowing visual tracking under the microscope
They introduced artificial signals mimicking foreign invaders to trigger immune response pathways
Using single-molecule localization microscopy, they captured the precise locations and movements of hundreds of thousands of individual protein molecules during activation
Advanced computational methods tracked how these molecules moved and interacted over time
Contrary to the established model of surface clustering, Gaus discovered that small membrane-enclosed sacks called vesicles inside the cell travel to the receptor, pick up the signal, and then depart again. She described this system as similar to "a docking port or an airport with vesicles like planes landing and taking off" 1 .
This mechanism explained the remarkable speed and efficiency of immune response—a rolling amplification process where a few receptors can activate a cell and trigger a massive immune defense.
| Aspect of Discovery | Previous Understanding | Gaus's Revelation |
|---|---|---|
| Signaling Initiation | Occurred at cell surface in molecular clusters | Initiated internally via traveling vesicles |
| Amplification Mechanism | Unknown how few receptors triggered massive response | "Rolling amplification" from vesicle docking system |
| Speed of Response | Difficult to explain rapid immune activation | Explained by continuous vesicle "landing and takeoff" |
| Resolution Possible | ~200 nm with conventional microscopy | ~10 nm with super-resolution microscopy |
Gaus's legacy includes not only discoveries but also the tools and facilities that enable ongoing research. The Katharina Gaus Light Microscopy Facility at UNSW houses state-of-the-art equipment that continues to advance biological imaging 2 .
| Tool/Technology | Function/Application | Biological Significance |
|---|---|---|
| Super-resolution Fluorescence Microscopy | Enables imaging of molecules as small as 10 nm | Reveals individual protein behavior in live cells |
| Leica Stellaris 8 Confocal | Advanced confocal imaging with spectral flexibility and FLIM capabilities | Studies molecular interactions and environmental changes |
| Zeiss Lightsheet 7 | Gentle, fast 3D imaging of large samples with minimal photodamage | Ideal for developmental biology and tissue imaging |
| MERSCOPE (MERFISH) | Maps and quantifies RNA species in tissues at single-cell resolution | Enables detailed spatial genomics analysis |
| High-Refractive Index Hydrogels | Stabilizes samples for tissue clearing and light sheet microscopy | Preserves tissue architecture during imaging 8 |
The facility provides comprehensive support from specimen preparation through image analysis, continuing Gaus's commitment to empowering researchers with cutting-edge technology.
Her development of specialized hydrogels for sample stabilization exemplifies her innovative approach to overcoming methodological challenges in microscopy 2 8 .
Gaus's toolkit extended beyond hardware to novel biochemical approaches. Her work with electrochemically controlled blinking of fluorophores demonstrated how physics and chemistry could combine to push the boundaries of biological imaging, allowing more precise quantitative STORM imaging through controlled fluorescence switching .
Katharina Gaus's impact extended far beyond her T-cell discovery. She founded and directed the EMBL Australia Node in Single Molecule Science at UNSW, creating an interdisciplinary research community that continues to thrive.
"Academically, I think she'll be known as the person who really first pushed to use tools like super-resolution to learn something new about important biology. The message was always 'what can we learn now?' not 'how can we show off this fancy kit?'"
Founded Cellular Membrane Biology Lab at UNSW
Established her independent research program
Received Gottschalk Medal from Australian Academy of Science
Prestigious award for early-career researchers
Promoted to Full Professor at UNSW at age 39
Recognized her research impact and leadership
NSW Science and Engineering Award
Excellence in Biological Sciences
NHMRC Elizabeth Blackburn Fellowship
Top-level research fellowship supporting her work
Khwarizmi International Award
International recognition for her contributions
Gaus was also deeply committed to mentoring and outreach, particularly encouraging schoolgirls to pursue science. She creatively explained immunology using analogies from the 1980s computer game Pacman, making complex concepts accessible and exciting to young minds 6 .
"We both knew we were incredibly privileged and with that privilege came a responsibility to help make the world better for others. Kat, with her incredible courage and selfless belief she could make a difference, did this by smashing straight through the barriers to change, allowing her to quickly and dramatically alter the research landscape both locally and internationally"
This pragmatic approach to technology—always focused on biological insight—defined her career. Former colleague Astrid Magenau recalled:
"She was the master of lateral thinking and had the ability to pull countless data sets together to transform them into high impact publications. Her fascination with the endless possibilities of microscopy led to her becoming the driving force to develop one of the first commercially available superresolution microscopes" 7 .
Katharina Gaus's work exemplifies how interdisciplinary approaches can revolutionize fields. By applying physics-derived imaging technologies to biological questions, she uncovered fundamental mechanisms of immunity that had eluded researchers for decades. Her discovery of the vesicle-based T-cell activation switch not only overturned established models but opened new avenues for therapeutic intervention in diseases ranging from autoimmune disorders to cancer.
More than her specific discoveries, Gaus built enduring infrastructure for scientific exploration—both in the form of cutting-edge facilities and in the community of researchers she mentored. The Katharina Gaus Light Microscopy Facility stands as a physical testament to her vision, while the many scientists she trained continue to advance her legacy of rigorous, innovative research 2 .
As Dr. Elizabeth Hinde, a former colleague, noted: "Kat pioneered super-resolution microscopy in the field of immunology and in Australia built a critical mass in single molecule biophysics... The key to Kat's success in building this great legacy, which will continue to thrive, was her open mindedness toward all research that was innovative, irrespective of whether it fell within her field, as well as her willingness to invest in new and novel technologies" 7 .
Though her career was cut short, Katharina Gaus's work continues to illuminate the hidden workings of our cells, proving that with the right tools and the courage to challenge established models, we can witness biology's most intimate secrets and harness that knowledge to improve human health.