A new ‘DNA microscope’ peers deep inside living cells

You could probably find a few biologists who are diehard protein partisans, and others who love lipids, but if a genie granted them one wish for what they could see inside living cells, most would pick DNA.

Joshua Weinstein of the Broad Institute of MIT and Harvard spent the last six years almost singlehandedly working to fulfill that wish, and on Thursday he unveiled the result: a “DNA microscope” that shows not only the locations of DNA (and its cousin, RNA) in a cell but also the precise nucleotide-by-nucleotide identity of each molecule.

The innovation, described in Cell, uses customized sequences of DNA about 30 nucleotides long, deposited into cells, to tag every DNA and RNA molecule in them. The tags latch onto the genetic material and then make hundreds of copies of the molecules. The copies collide and undergo chemical reactions, producing new paired nucleotide sequences. A DNA sequencer decodes these sequences. Finally, a computer algorithm reconstructs the molecules’ original locations in the cells along with its nucleotide sequence.

Electron microscopes, too, can see DNA in cells, and DNA sequencers can determine the A’s, T’s, C’s, and G’s (nucleotides) it’s made of. But the DNA microscope is the first instrument that simultaneously reveals both — where an RNA or DNA molecule is, down to individual cells, and what its sequence is — all without specialized equipment. (DNA sequencers have become so common in biology labs they don’t count as “specialized” anymore.)

The DNA microscope can see other molecules inside cells thanks to the fortuitous fact that DNA can label, or attach to, those other molecules. DNA microscopy can therefore determine the location and identity of antibodies, receptors, molecules on a tumor cell that immune cells attack, and more. Weinstein has so far used it to image human cancer cell lines and plans to apply the technology to tumors and the immune cells that infiltrate them, he said, which might one day guide immunotherapy.

Almost unheard of in this era of collaborations that are often larger than a soccer team, Weinstein, a postdoctoral fellow, worked virtually alone at the lab bench, advised by the Broad’s Aviv Regev and Feng Zhang. The Broad has applied for a patent on the invention.