Imaging the Imperceptible

Microscopy advances set the stage for mobile disease detection, nimble nanostructures and more.


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Photo Credits: Basanta Bhaduri and Gabriel Popescu, University of Illinois at Urbana-Champaign

This colorful donut created using spatial light interference microscopy (SLIM) is a map of the changes in a red blood cell’s outer membrane. Measuring fluctuations over time, researchers found that the membrane stiffens as red blood cells age, impeding cell operation. Superficially, the cells look healthy, but they slowly lose functionality over time.

The finding impacts blood that is stored over time. In the U.S., nearly 14 million units of blood are collected and stored annually with an estimated shelf life of 42 days. The SLIM imaging method could offer a way to monitor stored blood before patients receive it.

Photo Credits: Yosuke Bando, Fei Chen, Dawen Cai, Ed Boyden and Young Gyu (CC BY-NC-ND 3.0)

What could disposable diapers have to do with microscopy? The polymer that absorbs wetness in a diaper is now a critical element of a new imaging approach called expansion microscopy. These mouse brain cells were treated with both the polymer and glowing dyes to help researchers pinpoint individual cells and trace neural pathways. The process is akin to drawing on a balloon and then blowing it up. A key advantage to expansion is the smooth extension of molecules as they move away from each other.

Zeroing in on the smallest parts of the brain could help researchers map the actual cells responsible for initiating disease. These maps could then become the basis for systematic lists of cells to target with therapeutic treatments.

Photo Credits: Carle Illinois College of Medicine; University of Illinois at Urbana-Champaign

This artist rendering is based on an image of deoxyribonucleic acid (DNA) taken with an atomic force microscope (AFM). DNA is the genetic blueprint for human life. The dark shadows in the deep pink wavy lines are the rungs of the DNA helix. They correspond to DNA’s major and minor grooves, where proteins interact with the DNA to carry out biological processes such as regulating gene expression. Examining DNA’s structure with and without proteins attached enable researchers to learn more about the dynamics that occur in our genomes during life processes.

AFM provides the image resolution needed to view DNA structures that are roughly 10 times the size of an atom or about a billionth of a meter. The AFM provides a map of a molecule’s topography by tapping a tiny probe along its surface. The microscope can also measure a molecule’s strength.

Photo Credits: Florin Group, UT Austin

Thermal noise to be exact. The 3-D view of this collagen fibril was created using thermal noise imaging, a technique that’s been around since 2001 but technical challenges hindered its development until 2016. To acquire this image, researchers added nanometer-sized beads to a tissue sample and shone a laser on the sample. The beads reflect the light and a detector compiles superfast snapshots of the nanobeads through a light microscope.

The imaging technique’s high resolution of soft nanoscale structures makes it possible to probe collagen samples, providing insights for improved designs of artificial skin or tissue.

NSF will continue to support researchers as they explore new ways to record ever-sharper images of minute matter. Their success will lead to unprecedented views of the submicroscopic realm and to solutions for challenging issues faced in the life sciences, medicine and manufacturing.

The images in this National Science Foundation gallery are copyrighted and may be used only for personal, educational and nonprofit/non-commercial purposes. Credits must be provided.

Photo Credits: Bahram Javidi, University of Connecticut

Princess Leia they’re not, but these optical signatures of healthy red blood cells (top row) and malaria-infected cells (bottom row) offer a rapid way to diagnose disease in remote areas. The signatures are extracted from holograms of the original cells taken with a 3-D-printed portable holographic field microscope.

After obtaining the holograms, users transfer the data over the internet to a remote computer for analysis. To classify cells, system algorithms compare samples against the known features of healthy cells and diseased cells. This process reduces the time to identify a condition from days to minutes.

Beyond field diagnosis, the holographic microscope could be used in hospitals and other clinical settings to analyze cells associated with cancer, hepatitis, heart disease and other conditions.

Photo Credits: Frances Allen, Rachel Thayer and Nipam Patel, Biomolecular Nanotechnology Center/qb3, UC Berkeley

Butterfly wings dazzle with their array of patterns and colors. A deep dive into their wings reveals the intricate nanostructures responsible for their stunning mosaics. The blue and red honeycombed columns in this image are nanostructures on an emerald-patched cattleheart butterfly wing. Researchers are studying how butterflies erect these nanostructures during development and how the insects modify the growth process to vary color across the wing or between species. Their studies could lead to creation of custom designed nanostructures using biological processes that may be more economical and adaptable than mechanical or chemical approaches. Fields from optics to medicine could benefit from such an advance.

To view these tiny optics, researchers use ion microscopy. Creating an image requires a beam of helium or neon ions. When the beam strikes a sample, it gives off electrons that are recorded by a detector. The results are crisp images depicting fine surface details.

Photo Credits: Electron Imaging Center for NanoMachines (EICN), CNSI at UCLA

This may look like a popular children’s ball, but it’s the virus that causes bluetongue disease, a viral infection that has killed about 2 million cattle in Europe over the past two decades. Using a cryo-electron microscope, researchers created a highly detailed 3-D image of the nanometer-sized virus. Understanding how the virus operates offers a pathway to designing antiviral drugs as well as new vaccines to control bluetongue and related viral infections in animals and humans.

Cryo-electron microscopy has fundamentally changed biology and biochemistry with its unprecedented view of life at the atomic scale. It creates images by pumping a beam of electrons through multiple frozen samples containing millions of proteins. Software combines 2-D images of each protein to reconstruct a 3-D structure. Joachim Frank, Richard Henderson and Jacques Dubochet, inventors of cryo-electron microscopy, earned the 2017 Nobel Prize in chemistry. NSF supported Frank’s imaging research beginning in 1984.

Photo Credits: Kristen M. Harris, University of Texas at Austin

This very busy hub is a collection of dendrites (yellow and orange), axons (green), synapses (red), astroglia (light blue) and microglia (dark brown) in the brain’s hippocampus region. These components and pathways transmit and receive impulses from one cell to another. An electron microscope, which uses a beam of electrons as a light source, recorded the raw data that was then analyzed to create 3-D reconstructions of the structures.

Researchers plan to collect images from a variety of brain regions and specimens as well as develop a new electron microscope that can peer into the inner workings of the smallest substructure of individual synapses. They’ll also build new computational modeling tools to learn how these tiny frameworks aid brain function.

Photo Credits: Mark B. Edlund, Science Museum of Minnesota/SCWRS

At one time, coverslips, mirrors and lenses ruled the world of microscopy. Today, atoms, ions and laser beams are among the key components that create crisp images of the miniature world of cells, molecules and nanostructures. As the following images show, microscopy is now both art and science, a blend of data and design. No small feat.

National Science Foundation (NSF) funding ensures researchers can continue to push the limits of microscopy. NSF provides state-of-the-art imaging tools to academic labs; supports efforts to develop new microscopy techniques; and funds training for young scientists and engineers in the field.

One NSF-funded team used an optical microscope to image these diatoms—microalgae with glass-like shells that grow as single cells or small colonies. They were found in Mongolia’s 1.5 million-year-old Lake Hovsgol as part of a biodiversity study. Diatoms are a primary tool to monitor water quality and their fossils help to decipher environmental history.

To learn more, go to

Photo Credits: Oleg D. Lavrentovich, Liquid Crystal Institute, Kent State University

A polarizing microscope caught this psychedelic liquid crystal film as it spread over the surface of glycerine. These are the same kinds of liquid crystals in smartphones and television displays. While liquid crystals have transformed display technology, new knowledge about how these crystals order themselves in both space and time is making possible next-generation cameras free of mechanical zoom. The knowledge is also making possible a material made of spider-like polymers that generates electricity so you can power a smartphone through your shoe.

Originally developed for mineralogy, polarized light microscopy is used to inspect liquid crystals and polymers. Filters called polarizers orient incoming light in a single direction. When this light hits liquid crystals, it can transmit key details about local crystal orientations.

Photo Credits: Rajashekar Iyer, Graduate Research Assistant, Cell & Developmental Biology, Martha Gillette Laboratory, University of Illinois at Urbana-Champaign

This delicate structure is a single brain cell (neuron) from the hippocampus, the area in the brain that contributes to memory formation and recall and learning. Visible are the cell’s outline and tentacles (filopodia) that form connections between brain cells. Researchers used superresolution confocal microscopy and green fluorescent protein (GFP) to capture this close-up. In a young, developing brain, once the filopodia form connections with other neurons, they disintegrate. However, when development goes awry, the filopodia persist. Studies exploring how neurons mature are helping researchers to understand what goes wrong in diseases of brain development.

To create this image, the microscope’s laser light source was focused on cells containing GFP. The beam activated the protein, causing the cells to emit light. A specialized imaging detector collected all of the emitted light, producing ultrasharp resolution. The spindly filopodia are about a hundredth the width of a human hair and about a thousandth wide.

Photo Credits: Hideo Otsuna, Ph.D.

Glowing red, green and blue, the nerve fibers in this five-day-old zebrafish provide a map of early brain development. The image was taken using FluoRender, an interactive visualization and analysis software for confocal microscopy data. Neurobiologists use the software to manipulate and measure structural anatomy on a range of organisms from fruitflies to mice.

Confocal microscopy uses a single point of light, usually a laser beam, to scan a sample into a series of optical sections, building up each image pixel by pixel. Fluorescent dyes enhance imaging by defining structures of interest.

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