On October 4, 2017, an emerging technique for structural visualization was brought to the world’s attention by the Royal Swedish Academy of Science. Developed by Jacques Dubochet, Joachim Frank, and Richard Henderson, cryo-electron microscopy, or cryo-EM, garnered one of chemistry’s highest honors for its ability to “visualize processes… never previously seen” in complex biological setups. Cryo-EM is lauded for its ability to characterize structures impossible to approach with traditional techniques. As this incredible technology matures, will other visualization methods grow obsolete?  

Cryo-EM is not the only visualization technique to win a Nobel Prize. A little over a century ago, another one was awarded—this time in physics—to Sir William Henry Bragg and his son William Lawrence Bragg. Not long after the discovery of x-rays, the Braggs began closing the gap between observed x-ray scattering patterns and the spatial arrangements of crystals they bounced off of. Thus, as more advanced mathematical analyses developed, it became possible to extrapolate a structure by shooting x-ray beams at its crystals. The field of x-ray crystallography has grown up quite a bit since then, but the question of whether or not it will continue to be relevant remains.

Nozomi Ando, a professor in Princeton University’s chemistry department, offers a unique perspective on the present and future of structural visualization. Situated at the confluence of a diverse set of fields, Ando’s lab develops x-ray based methods to elucidate dynamic enzyme interactions. These methods differ from crystallography in that they are captured in less austere conditions; often performed in solution, techniques like small angle x-ray scattering (SAXS) can capture a more lifelike picture of enzyme chemistry. In an interview with Innovation, Ando noted that although these methods tend to have inherently lower resolution than x-ray crystallography, they are “complementary” and can be used in various combinations to piece together the structures and interactions of complex enzymes.

As structural biology moves toward dynamics... x-ray based methods could potentially be much better suited.

According to Ando, x-ray based methods aren’t going away anytime soon. What she terms the “workhorse of structural biology,” x-ray crystallography continues to crank out novel protein structures at a mesmerizing rate. The amount of structures entered into Protein Data Bank each year, most often obtained through crystallography, currently shows no signs of plateauing. Not only are x-ray methods much more advanced than cryo-EM ones at present, but they also confer subtle advantages. As structural biology moves toward dynamics, Ando notes that x-ray based methods could potentially be much better suited towards this end, as they do not necessarily require samples to be frozen and can therefore facilitate the observation of more kinetic interactions.

Cryo-EM fits as another puzzle piece in the growing structural toolkit at our disposal. Ando paints it as somewhat of a bridge between the cell and the protein, providing a specific “wavelength” of resolution simultaneously too large and too small for other methods to capture. While x-ray crystallography confers visibility primarily at the protein level, Ando says that cryo-EM can be used to shed light on “large biological assemblies” too large and heterogeneous to crystallize. She envisions that progress in each respective technique will tend towards its advantages, and that each field will thus continue to contribute something distinctly valuable to scientific techniques for the foreseeable future.

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Sarah Perkins