New microscope captures awesome animated 3D movies of cells at high resolution and speed

Nobel laureate Eric Betzig's radical invention merges high-speed, non-invasive bioscanning and astronomy's adaptive optics
April 20, 2018

HHMI Howard Hughes Medical Institute | An immune cell explores a zebrafish’s inner ear

By combining two state-of-the-art imaging technologies, Howard Hughes Medical Institute Janelia Research Campus scientists, led by 2014 chemistry Nobel laureate physicist Eric Betzig, have imaged living cells at unprecedented 3D detail and speed, the scientists report on April 19, 2018 in an open-access paper in the journal Science.

In stunning videos of animated worlds, cancer cells crawl, spinal nerve circuits rewire, and we travel down through the endomembrane mesh of a zebrafish eye.

Microscope flaws. The new adaptive optics/lattice light sheet microscopy (AO-LLSM) system addresses two fundamental flaws with traditional microscopes. They’re too slow to study natural three-dimensional (3D) cellular processes in real time and in detail (the sharpest views have been limited to isolated cells immobilized on glass slides).

And the bright light required for imaging causes photobleaching and other cellular damages. These microscopes bathe cells with light thousands to millions of times more intense than the desert sun, says Betzig — damaging or killing the organism being studied.

Merging adaptive optics and rapid scanning. To meet these challenges, Betzig and his team created a microscopy system that merges two technologies: Aberration-correcting adaptive-optics technology used by astronomers to provide clear views of distant celestial objects through Earth’s turbulent atmosphere; and non-invasive lattice light sheet microscopy, which rapidly and repeatedly sweeps an ultra-thin sheet of light through the cell (avoiding light damage) while acquiring a series of 2D images and building a high-resolution 3D movie of subcellular dynamics.

Zebrafish embryo spinal cord neural circuit development (credit: HHMI Howard Hughes Medical Institute)

The combination allows for the study of 3D subcellular processes in their native multicellular environments at high spatiotemporal (space and time) resolution.

Desk version. Currently, the new microscope fills a 10-foot-long table. “It’s a bit of a Frankenstein’s monster right now,” says Betzig. His team is working on a next-generation version that should fit on a small desk at a cost within the reach of individual labs. The first such instrument will go to Janelia’s Advanced Imaging Center, where scientists from around the world can apply to use it. Plans that scientists can use to create their own microscopes will also be made freely available.

Ultimately, Betzig hopes that the adaptive optical version of the lattice microscope will be commercialized, as was the base lattice instrument before it. That could bring adaptive optics into the mainstream.

Movie Gallery: Lattice Light Sheet Microscopy with Adaptive Optics 

Endocytosis in a human stem cell derived organoid. Clathrin-mediated endocytosis in vivo. Clathrin localization in muscle fibers.