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3D Action Film Stars Cancer Cell as the Villain

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For centuries, microscopes have brought to light the otherwise invisible world of the cell. But microscopes don’t typically visualize the dynamic world of the cell within a living system.

For various technical reasons, researchers have typically had to displace cells, fix them in position, mount them onto slides, and look through a microscope’s viewfinder to see the cells. It can be a little like trying to study life in the ocean by observing a fish cooped up in an 8-gallon tank.

Now, a team partially funded by NIH has developed a new hybrid imaging technology to produce amazing, live-action 3D movies of living cells in their more natural state. In this video, you’re looking at a human breast cancer cell (green) making its way through a blood vessel (purple) of a young zebrafish.

At first, the cancer cell rolls along rather freely. As the cell adheres more tightly to the blood vessel wall, that rolling motion slows to a crawl. Ultimately, the cancer cell finds a place to begin making its way across and through the blood vessel wall, where it can invade other tissues.

This video was made using the latest imaging advance from Eric Betzig, a Nobel Laureate at the Howard Hughes Medical Institute’s Janelia Research Campus, Ashburn, VA, and colleagues. As described recently in the journal Science, their creation starts with an imaging device previously developed by Betzig called lattice light sheet microscopy [1]. It’s known for generating extremely thin sheets of light that speed up and extend image acquisition to produce stunningly vivid images of living cells over time and space.

But it can be challenging for lattice light sheet microscopy to zoom in on an individual cell inside the body because the other nearby cells scramble and distort light. To solve that problem, Betzig’s team, including Gokul Upadhyayula, Harvard Medical School, Boston, turned to adaptive optics—the same technology used by astronomers to provide clear views of distant celestial objects through Earth’s turbulent atmosphere.

This approach relies on a bright point of laser light acting as a “guide star.” When shone within an area of interest, distortions in the guide star image provide information about the optical aberrations. That makes it possible to remove them, producing a crystal-clear picture.

Their new hybrid microscope now sweeps ultra-thin sheets of light across a sample to capture 3D images. Those sweeps capture a series of 2D images, which, when strung together, create dynamic 3D movies.

In the video, Benjamin Martin, Stony Brook University, Stony Brook, NY, wanted to understand how cancer cells behave circulating through the bloodstream. Martin and colleagues injected fluorescently labeled human breast cancer cells into young zebrafish, which are naturally transparent, and then simply watched what happened.

This new microscope currently fills a 10-foot table and is available only on the Janelia campus. But the researchers hope to have commercial versions of a more manageable size and cost in the future.

In the meantime, Betzig and colleagues have already amassed an impressive collection of movies starring sugar-gobbling immune cells, neural circuits developing within the spinal cord, and much more. Take a look and see the cellular world in a new way.

References:

[1] Observing the cell in its native state: Imaging subcellular dynamics in multicellular organisms. Liu TL, Upadhyayula S, Milkie DE, Singh V, Wang K, Swinburne IA, Mosaliganti KR, Collins ZM, Hiscock TW, Shea J, Kohrman AQ, Medwig TN, Dambournet D, Forster R, Cunniff B, Ruan Y, Yashiro H, Scholpp S, Meyerowitz EM, Hockemeyer D, Drubin DG, Martin BL, Matus DQ, Koyama M, Megason SG, Kirchhausen T, Betzig E. Science. 2018 Apr 20;360(6386).

Links: 

Video: Lattice Light Sheet Microscopy

Video: Adaptive Optics Microscopy

Betzig Lab (Howard Hughes Medical Institute, Ashburn, VA)

NIH Support: National Cancer Institute