Using sheets of light to scan cells, a new microscope can capture real-time 3D videos of what's happening inside cells down to the molecular level—feat once thought impossible.

The inventors of the new device—including 2014 Nobel Prize winner Eric Betzig, teamed up with 30 teams of biologists over the past year to produce extraordinary 3D movies of biological events from the movements of individual proteins to the development of entire animal embryos over the course of many hours.

Sheets of Light

Betzig shared this year's Nobel Prize in Chemistry for developing microscope techniques that can image molecules and other items smaller than a wavelength of light. But these strategies came with tradeoffs. For example, imaging cells at high resolution in three dimensions usually means subjecting cells to significant damage from light. And the process was still too slow to catch many cellular activities in real time.

This new microscope, outlined today in the journal Science, builds on advances in what's called light-sheet microscopy, in which sheets of light scan the targets. Conventional light sheets are too thick to illuminate details smaller than cells, though. So Betzig and his colleagues used ultra-thin sheets as little as 250 nanometers (billionths of a meter) wide.

The new microscope can achieve resolutions of up to 230 nanometers and record at up to 1,000 frames per second, Betzig says. And crucially, the light sheets spread light energy in such a way to minimize damage to any single point in a specimen.

Scientists have used the new microscope to study embryonic development in nematodes and fruit flies, trace the pathways of nerve cells that form synapses in the brain, and follow the progress of proteins that clump together to cause disease.

"This really lets you look at the dynamic processes in cells in 3-D non-invasively," says Betzig, an engineering physicist at the Howard Hughes Medical Institute's Janelia Research Campus in Ashburn, Va.

"We can go small for single-molecule imaging, or move up to study multiple organelles interacting inside a cell, or how cells interact with their environments and other cells," Betzig says. "On the biggest scale, we can look at developmental biology. I'm amazed at my four children, and all the events that had to happen in a precise way for the perfection that has come out at the end. We can study these events in real time."

preview for Microscope Captures 3-D images of Cellular Activity in Real Time

Transformative Technology

Two of the new microscopes have been deployed to Harvard University and the University of California at San Francisco. At Harvard, cell biologist Tomas Kirchhausen is now producing movies to watch how cells eat, how viruses enter cells, and how cells change in shape and size as they divide.

"This is a transformative technology," Kirchhausen says. "Everybody will now have to start using it. The data they can obtain with it will quickly replace many other instruments currently used in the field. I'm ready to sell my other microscopes on eBay and use this."

The scientists developed a complete set of documents for developing the lattice light-sheet microscope; "anyone who wants to make one can get a license with the Howard Hughes Medical Institute," Betzig says. Optical systems manufacturers Carl Zeiss in Germany and Intelligent Imaging Innovations in Denver have licenses to produce clones of the prototype.

Betzig and his colleagues hope to advance their microscope further by peering deeper into tissues and organisms, using deformable mirrors and adaptive optics techniques first developed for use in astronomy to overcome the visual interference caused by intervening matter.