Watch the cell's machinery move without adding dyes that change its behavior
At Stanford, a new microscope called iISM has quietly expanded what it means to see life — watching living cells at 120-nanometer resolution without the chemical markers that have long defined biological imaging. By weaving together two established techniques into something greater than either alone, researchers have found a way to observe the cell's inner world in motion, undisturbed and undimmed. It is a reminder that some of science's most consequential advances arrive not as ruptures, but as careful acts of synthesis — seeing more clearly by learning to look differently.
- Fluorescent labels, the workhorses of cell biology for decades, carry hidden costs: they fade, they interfere, and they limit how many structures a scientist can watch at once.
- iISM breaks that constraint by scattering laser light off cellular structures directly, requiring far less illumination power and leaving the living cell largely undisturbed.
- An array of dozens to hundreds of tiny sensors replaces the single detector of conventional microscopes, building sharper images from overlapping viewpoints simultaneously.
- Nobel laureate W.E. Moerner and postdoctoral researcher Michelle Kueppers are already fielding collaborators studying cancer drug delivery, malaria-infected blood cells, and plant-fungi-bacteria dynamics.
- The team is now working to refine iISM and distribute it broadly, wagering that label-free clarity at this scale will unlock biological questions fluorescence alone could never answer.
A Stanford laboratory has built a microscope that watches living cells at a resolution finer than 120 nanometers — without ever staining or chemically marking what it sees. The instrument, called iISM, achieves this by combining two existing techniques: one that detects light scattered off tiny cellular structures, and another that replaces a single detector with a grid of dozens to hundreds of tiny sensors, all observing the same region at once. The result is sharper, higher-contrast images assembled from many overlapping perspectives rather than one.
The effort was led by W.E. Moerner, a Stanford chemistry professor and 2014 Nobel laureate in fluorescence microscopy, alongside Michelle Kueppers, a postdoctoral researcher whose doctoral work centered on the scattering method at the instrument's core. Kueppers was careful to frame iISM not as a rival to fluorescence microscopy but as a complement — fluorescence remains powerful for identifying specific molecules, but it carries real limitations: signals fade, only a few structures can be marked at once, and the dyes themselves can subtly alter cellular behavior. iISM sidesteps these problems, using lower laser power, tracking many structures simultaneously, and sustaining observation over longer periods without signal loss.
Published in February 2026 in Light: Science and Applications, the research has already drawn collaborators from across Stanford. One team is using iISM to watch plant cells, fungi, and bacteria interact in real time. Another is following a cancer drug as it crosses a cell membrane. A third will study how red blood cells deform under malaria infection. Kueppers described iISM as a broad platform rather than a niche instrument — one the Stanford team intends to refine and make widely available, confident that seeing living cells in such detail, without harming them, will open discoveries that fluorescence alone could not reach.
A Stanford laboratory has built a microscope that watches living cells at a resolution finer than anything achieved before without chemical markers. The instrument, called Interferometric Image Scanning Microscopy or iISM, can resolve structures down to 120 nanometers across—small enough to see how the cell's molecular machinery moves and changes in real time, without the scientist having to paint those structures with fluorescent dyes.
The breakthrough comes from marrying two existing microscopy techniques. One uses a laser to illuminate a cell; the light scatters off tiny structures inside, and a second laser amplifies that faint scattered signal enough to detect it. The other technique borrows from advanced confocal microscopes, which traditionally used a single detector to focus on one target. Stanford's team instead deployed an array detector—tens to hundreds of tiny sensors arranged like a grid—all watching the same region of the cell simultaneously. The result is sharper images with better contrast, built from many overlapping viewpoints rather than one.
W.E. Moerner, a Stanford chemistry professor who won the Nobel Prize in 2014 for work on fluorescence microscopy, led the effort alongside Michelle Kueppers, a postdoctoral researcher whose doctoral work focused on the scattering technique. Kueppers described the approach as complementary rather than competitive. Fluorescence microscopy has driven decades of biological discovery and remains powerful for identifying specific molecules. But it has limits: scientists can usually mark only a handful of structures at once, the fluorescent signals fade over time, and the dyes themselves can alter how the structures behave. iISM sidesteps those problems. It uses much less laser power, so it causes less light-related damage to living cells. It can track many structures at once and follow them for longer stretches without the signal degrading.
The microscope is not a replacement for fluorescence methods but rather a partner. Moerner noted that the new instrument offers "a wonderful look into these complex little cellular boxes that drive our life," letting researchers watch structures move and interact in their natural context. Kueppers emphasized that combining the molecular specificity of fluorescence with the label-free dynamics of iISM opens doors to questions that have been hard to tackle before.
The research, published in February 2026 in Light: Science and Applications, has already attracted collaborators across Stanford. One team is using iISM to observe how plant cells, fungi, and bacteria interact in real time. Another is watching a cancer drug cross the cell membrane. A third project will examine how red blood cells deform when infected with malaria. Kueppers stressed that iISM is not a niche tool but a broad platform with applications across the life sciences—disease mechanisms, drug development, microbial interactions. The Stanford team is now working to refine the technology further and make it available to the wider scientific community, betting that the ability to see living cells in such detail without damaging them will spark discoveries that fluorescence alone could not reveal.
Notable Quotes
You can see the tiny structures and machines in the cell moving, changing, and interacting without having to add fluorescence to observe them.— W.E. Moerner, Stanford chemistry professor
If we use the strengths of fluorescence for molecular specificity and the strength of iISM for label-free context and dynamics, we can really start tackling questions that have been difficult to address before.— Michelle Kueppers, postdoctoral researcher
The Hearth Conversation Another angle on the story
Why does it matter that you don't need fluorescent labels? Isn't that just a technical detail?
It's actually the difference between watching a cell live and watching a cell that's been altered by the observation itself. When you add fluorescent dyes, you're introducing foreign molecules that can change how the structures you're trying to study actually behave. You're also limited—you can usually only mark a few structures at once. With iISM, you see everything at once, in context, the way it actually is.
But you said it doesn't reach the same resolution as some other microscopes. So what's the trade-off?
You're trading ultimate resolution for something more valuable in many cases: the ability to watch living cells for hours without damage, and to see multiple structures interacting simultaneously. Some specialized fluorescence techniques can go finer, but they're like looking at a single labeled molecule through a straw. iISM is like turning on the lights in the whole room.
The array detector—using many sensors instead of one—that's the key innovation?
It's the key to making this work. It's like the difference between one eye and two eyes. Our brain uses two viewpoints to understand depth and separate foreground from background. iISM uses tens or hundreds of viewpoints from the array detector to build a much sharper, more detailed image. The math to combine all those views is what took real work.
What happens next? Is this going to be in every lab?
Not immediately. Right now it's at Stanford, and they're collaborating with other researchers there. But the team is working to make it available more broadly. The applications are already clear—watching how drugs enter cells, how infections change cell shape, how microbes interact with plants. Once other labs can build and use it, I think you'll see it become standard for any question where you need to watch living cells without damaging them.