Most Sensitive Microscope Sees Cells Change in Real Time

A microscope designed by this year’s Nobel Prizer winner harnesses ultrathin sheets of light to peer into living cells, tracking everything from a single protein’s moves to embryo formation.

The development, outlined today in the journal Science, goes beyond the super resolution tools that led to Eric Betzig being awarded the 2014 Nobel for chemistry. While his earlier work allowed scientists to study cell structure with greater clarity, the new device allows three-dimensional imaging of cells as they change over time.

The result: Movies made at a molecular level that allow an inside peek at how single cells divide, or are penetrated by a virus. The microscope was designed as a basic research tool, used by scientists to look at fruit flies, worms and zebra fish. The results, though, hold promise for helping understand how cancer metastasizes and birth defects occur.

“We can slice and dice like a deli,” Betzig said in a telephone interview. “We can track and see the production of single molecules, trace them and see how they assemble into structures. It’s going to be a go-to tool for live imaging.”

The Science report details how the new technology works, and its use during collaborations with 20 teams of biologists visiting the Howard Hughes Medical Institute’s Janelia Research Campus in Ashburn, Virginia.

In an interview, Betzig used an analogy to Google Maps to explain how different microscopes work.

Electron microscopes are good for looking at molecular structures, providing the type of map that Google might offer a user trying to figure out where something is in Manhattan. The super resolution microscope can highlight all the Starbucks or different stores, one at a time.

Real-Time Action

The lattice light sheet, the device explained in the Nature report, shows 3D images of what is occurring in real-time in those locations.

“It’s not good to park in one plane and get a 2D image,” he said. “You need a continuous picture of how things are evolving, and not a slow series of snapshots where you don’t know how frame A is related to frame B.”

Betzig and his collaborators manipulated the light that is needed to create an image to reduce the damage it does to the cells. Instead of casting light down, they brought it in through the side to sweep through a specimen.

The added element of speed helped protect the cells by scanning faster than the time it takes cells to evolve, about 1,000 planes a second.

Reducing Damage

The speed reduced the damage from the light and allowed them to more clearly track movement, the researchers found. In a final test, the researchers invited other scientists to experiment with the microscope free of charge. The result is they are only just now starting to uncover the microscope’s potential applications, said Kai Wang, a postdoctoral researcher who worked on the microscope.

“This is not a single imaging technique,” he said. “It’s an imaging platform.”

Betzig said it’s not clear yet how big of an impact the new instrument will have.

“Every new invention is like a baby,” he said. “You think it may cure cancer or become the president, but in the end you’re happy it just stays out of jail. I do think this could have a bigger impact than the one that got me the Nobel.”

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