For hundreds of years, images of cells have come from isolated specimens sitting on glass slides, removed from their intricate and subtle cellular universes within living organisms. Now, using a new imaging technique described in Science on Thursday, living cells can be filmed in high-resolution and 3-D, producing stunning videos of their fully animated worlds.
“Studying the cell on a coverslip is like watching a lion in the zoo—you’re not exactly seeing their native behaviors,” says physicist Eric Betzig. Using the new microscope “is like watching the lion chase an antelope on the savanna. You’re finally seeing the true nature of cells.”
Betzig, who won the Nobel Prize in Chemistry in 2014, led a team from the Howard Hughes Medical Institute Janelia Research Campus that combined two older microscopy techniques and three separate microscopes to create the powerful new “frankenscope.” (Related Article: How Many Cells Are in the Human Body—And How Many Microbes?)
From Space to Cells
Photographing cells within a living organism is hard, even when that organism is a transparent zebrafish like the ones used for the new study. In particular, two optical issues posed a difficult challenge for Betzig.
The cells on the surface of the fish act like water on a car windshield, obscuring and scattering any light that tries to penetrate them. The further you look into the organism, the worse the distortion becomes.
To help correct for this, Betzig borrowed a technique from astronomers called adaptive optics. With telescopes on Earth, our planet’s atmosphere similarly distorts images taken of distant objects in space. Adaptive optics measures that distortion and corrects for it, offering clear, unwavering pictures of stars, galaxies, and other cosmic objects.
“If you can measure how the light is warped, you can change the shape of the mirror to create an equal and opposite distortion that then cancels those aberrations,” explains Betzig.
The other challenge is that with microscopes, traditional ways of imaging used points of light millions of times brighter than the Sahara on a sunny day, creating a harsh environment that can damage or even kill the cells scientists are trying to study.
“Life wasn’t really evolved to take that kind of abuse. If you don’t outright kill the cell, you’re always left wondering, What did I do to this poor thing, and am I really seeing it the way it normally is?” says Betzig.
Incorporating a technique he helped develop in 2014 called lattice light sheet, the new microscope uses a sheet of light to scan the cells like a Xerox machine. This allows for the cell to be imaged in a faster, gentler, and more detailed way.
Marrying that scanning approach with adaptive optics creates images that are then combined into the highly detailed 3-D models.
For now, the microscope can only peer into transparent organisms. More opaque surfaces, like human skin, offer a greater challenge for the future. But seeing cells in their natural context is more than just for show. As the technology evolves, the ability to study both healthy and diseased cells, and understand the difference between them, could impact medical research and drug testing.
In the meanwhile, it’s easy to get lost in the first crop of awe-inspiring videos. Seeing the images for the first time, Betzig had this response: “You can quote me on this: It was f---ing awesome.”