Stanford researchers have built a one-of-a-kind research microscope that images living cells in real time without fluorescent labels. Called interferometric image scanning microscopy (iISM), the instrument combines interferometric scattering microscopy with an adapted image-scanning method to produce images at about 120 nanometers resolution, according to the Stanford team’s 2026 report.
What Stanford’s new microscope is
iISM is an emerging live-cell imaging method rather than a commercial microscope model. It is designed to show the movement, shape and interactions of many structures inside living cells over extended observations, while preserving a wider view of the cell than a technique aimed at one fluorescently tagged target.
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A resolution of 120 nanometers means the reported instrument can distinguish features separated on roughly a 0.12-micrometer scale under the researchers’ imaging conditions. That is a spatial measurement, not molecular identification: the microscope does not automatically tell researchers which molecule produced a feature. Its value is seeing unlabeled cellular structure and dynamics in context.
How iISM produces a label-free image
1. Scattered light carries structural information
A laser illuminates the cell. Tiny structures inside it scatter a small portion of that light, including structures that have not been tagged with a dye or fluorescent protein.
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2. Interferometry boosts the weak signal
A second beam is used to amplify the weak scattered signal through interference, making changes in the cell’s structure detectable. This is the interferometric-scattering part of the instrument.
3. Scanning and an array detector improve contrast
The system adapts image-scanning microscopy and uses an array detector to collect multiple views of the same area. Those views are combined computationally into a sharper, higher-contrast image than a single detected view would provide.
The result is a continuously updated picture of unlabeled cell structures. Researchers can follow organelle movement, structural changes and interactions without repeatedly adding labels to the sample.
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Why avoiding fluorescent labels matters
Fluorescence microscopy is powerful because a label can identify a particular protein, organelle or chemical process with high molecular specificity. However, the experiment normally highlights only the structures that were labeled, and fluorescent signals can bleach during prolonged illumination. A label can also alter the behavior of the system being studied, depending on the probe and the biological target.
iISM approaches the problem from the opposite direction. It does not provide the same molecular specificity, but it can display many unlabeled structures at once and follow them for long periods without fluorescent-label bleaching. That broader structural context can reveal events that would be missed if the experiment were organized around a single tagged target.
“This new microscope provides a fantastic new view into the cell, where 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, Harry S. Mosher Professor of Chemistry at Stanford, said.
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Michelle Kueppers, who is also associated with the work, described the method this way: “This is not a niche technique.” The claim reflects the range of biological questions the team is exploring, not a statement that iISM has already replaced established microscopy platforms.
iISM compared with fluorescence microscopy
The two methods answer different questions and can be used together. Fluorescence can identify a selected molecular target; iISM can supply a wider, label-free view of what the cell is doing around it.
| Comparison point | iISM | Fluorescence microscopy |
|---|---|---|
| Labels required | No fluorescent label is required; the image is based on intrinsic light scattering. | Usually requires a fluorescent dye, tagged protein or another fluorescent probe. |
| Molecular specificity | Lower specificity: structures are visible, but the method does not identify their molecules by itself. | High specificity for the targets selected by the label. |
| Structures visible at once | Many unlabeled structures can appear together, preserving broader cellular context. | Primarily the labeled structures and channels selected for the experiment. |
| Long observations and bleaching | Supports extended observation without fluorescent-label bleaching. | Fluorescent signals can bleach during prolonged illumination; the risk depends on the label and imaging conditions. |
| Resolution | About 120 nanometers in the Stanford researchers’ 2026 report. | Some specialized fluorescence methods can achieve finer resolution, depending on the technique and setup. |
| Laser exposure and imaging speed | Comparative exposure and speed figures were not stated in the Stanford report. | Exposure and speed vary substantially by microscope, fluorophore, illumination strategy and acquisition mode. |
| Best-known strength | Label-free structural context and dynamics in living cells. | Molecularly specific tracking of selected components. |
In practice, a lab may use iISM to locate and understand a dynamic event, then use fluorescence to identify a particular component involved in that event. The Stanford report does not establish a universal winner on phototoxicity, speed or laser dose; those results depend on the complete optical setup and experiment.
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What Stanford has demonstrated so far
Plant cells
The team has used the instrument to observe structures in living plant cells, where unlabeled compartments and their movements can be followed in context.
Fungi and bacteria
Reported experiments include real-time interactions involving fungi and bacteria. Label-free viewing is useful when adding a probe could complicate a fast-changing interaction or when researchers need to see several participants at once.
Cancer-drug uptake
Stanford researchers have also observed cells taking up a cancer drug. The method can show the surrounding cellular response and changing structure rather than limiting the view to a fluorescently marked drug or organelle.
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Planned malaria research
The researchers plan to observe red-blood-cell shape changes during malaria infection. This is a planned research application, not evidence that iISM is already a malaria diagnostic.
What the microscope cannot yet claim
- It is a research instrument and emerging imaging method, not a consumer microscope.
- The Stanford report does not describe a retail model, price, commercial supplier or routine service for outside customers.
- It is not presented as a clinical diagnostic or a patient-ready test.
- Its approximately 120-nanometer resolution does not provide the molecular specificity of a fluorescent label.
- Performance will depend on the sample, optical alignment, detector, scanning conditions and image-processing workflow; the report does not provide a universal speed or exposure specification.
Stanford says the researchers hope to make the technology more widely available to scientists. Until that happens, access is likely to depend on research collaborations or specialized imaging facilities rather than an off-the-shelf purchase.
Why this matters for cell biology
Many important cellular events are both spatial and temporal: an organelle moves, a membrane changes shape, a pathogen contacts a host cell, or a drug enters and redistributes through the cell. A method that supplies structural context for long observations can expose relationships that a narrowly labeled image may miss. iISM’s role is therefore complementary: it broadens the view, while fluorescence remains the stronger choice when the central question is exactly which molecule is present.
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