Sometimes what looks like a fundamental physical limitation isn’t so insurmountable after all. An example is the diffraction limit: Light can’t be focused to a spot smaller than half its wavelength, so it might seem to be impossible to use visible light to image features smaller than 200 nm. But researchers took on the diffraction limit and won, as highlighted by the 2014 Nobel Prize in Chemistry (see Physics Today, December 2014, page 18). The three laureates—Eric Betzig, Stefan Hell, and William Moerner—and others developed ingenious ways to use optical fluorescence microscopy to obtain images with resolution of around 20 nm. And the resolution revolution was just getting started.
One can see a lot at 20 nm resolution. In biological systems—the most appealing imaging target because of all their unknown nanoscale complexity—that’s the scale of organelles, protein complexes, and many other supramolecular structures (see, for example, Physics Today, May 2015, page 14). But a lot remains unseen. Many important features are an order of magnitude smaller, including the shapes and conformations of individual proteins. And still images completely leave out what’s arguably the most important thing about living systems: the way they change over time.
In the years since the Nobel, superresolution researchers have pushed to improve the resolution in both space and time. They’ve now reached the point of achieving nanometer and millisecond precision simultaneously—good enough to watch the motions of proteins in real time—as shown in new work by two groups in Heidelberg, Germany, one led by Jonas Ries of the European Molecular Biology Laboratory (EMBL)1 and the other led by Hell at the Max Planck Institute for Medical Research.2 Both groups used MINFLUX, a technique Hell and colleagues unveiled3 in 2017, and both studied the motor protein kinesin, illustrated in figure 1, whose job it is to carry cargo from place to place inside a cell.
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