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Scientists marry two powerful techniques to pinpoint locations of individual molecules in their cellular neighborhoods

Researchers expect the new method to answer fundamental questions in biology and materials science.
image of molecule

 

Scientists have combined two powerful microscopy techniques to make images that pinpoint, for the first time, the identities and precise locations of individual proteins within the detailed context of bacterial cells. This information is crucial for learning how protein molecules work together to organize cell division.  The new hybrid method, called Correlated Imaging by Annotation with Single Molecules, or CIASM (pronounced “chasm”), was developed by Peter Dahlberg, a postdoctoral researcher in the lab of Professor W. E. Moerner at Stanford University.  

It’s a variation on a technique called low temperature single-molecule microscopy, invented by Moerner three decades ago, which attaches glowing labels to molecules so they can be individually identified.  Dahlberg found a way to make this type of fluorescence imaging work at sub-freezing temperatures so the same samples could also be examined with cryogenic electron tomography (CET). CET uses streams of electrons to make 3D images of flash-frozen cells and their components at near-atomic resolution. Combining CET with the fluorescent imaging allows scientists to see the tagged molecules in the context of the surrounding cell, a crucial perspective for understanding their role in the cellular machinery.

“This is a big leap for biology, and I think there are many, many systems that will benefit from this kind of imaging,” said Stanford Professor Lucy Shapiro, whose research group participated in the study.

Even in relatively simple bacterial cells, location is everything, said Saumya Saurabh, a postdoctoral researcher in Shapiro’s lab who played a leading role in the research. “People tend to think of bacteria as sacks of proteins with no organization,” he said. “But it turns out that’s not true, and in fact many of the molecules in bacteria are precisely located in both space and time. If they’re not in the right position, the cell dies. What Pete’s work is finally allowing us to do is look inside with molecular resolution and find out when and where these molecules are located with respect to each other.”

For this study, proteins were labeled with fluorescent tags, then samples were frozen and taken to the Stanford-SLAC Cryo-EM facilities for CET imaging directed by Wah Chiu, a professor at Stanford and SLAC.

“It is the early days of combining the two methods, and we are excited to explore more collaborations linking light and electrons,” Chiu said. “This hybrid imaging approach has the potential to uncover structures of molecular components involved in key biological processes in cells spanning all domains of life.”

Read the full article on SLAC 

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