Capturing biomolecules in the middle of their movements

Jacques Dubochet, Joachim Frank (both of whom are biophysicists) and Richard Henderson’s (a molecular biologist) work on cryo-electron microscopy (cryo-EM) is an intriguing breakthrough in the field of chemistry. This is a new, better and simpler way of imaging tiny frozen molecules. This novel ‘cool method’ is now routinely used to produce 3D biomolecular structures. In this method, electron beams are employed to photograph the smallest cell structures.

As a result, biomolecules can now be captured in the middle of their movements. This enables scientists to observe previously unseen processes and capture minute details of the mechanisms involved inside cells, proteins and viruses. These were earlier inaccessible even with the usual electron microscopes, where the beams could even damage the samples observed.

It is to be noted that earlier, even with electron microscopes, complex biomolecules — including proteins, DNA and RNA — were terra incognita in biochemical maps, since the powerful electron beam (used in such microscopes, the higher the electron energy the better the resolution) had a tendency to destroy the biological material. This resulted in long-held perception that electron microscopes unveil the images of only dead biological matter. Richard Henderson, however used an electron microscope in 1990 to unravel a 3D image of a protein at individual atomic resolution, considered an epoch making discovery. Joachim Frank, while developing methods for processing details in the electron microscope's usual 2D fuzzy images was able to achieve a clear 3D structure. Later, Richard Henderson succeeded in presenting the structure of a bacterial molecule at atomic resolution. Jacques Dubochet’s contribution was the use of water! He developed a technique more than 30 years ago to rapidly supercool water so that it solidifies (as a liquid) around biological samples. This enables the molecules to preserve their shape even in vacuum.

Flash-frozen molecules

A recent application of cryo-EM was to the Zika virus. When it was suspected that the Zika virus was causing the epidemic damaging brains of newborns, cryo-EM was used to visualise the virus. The ultra-sensitive cryo-EM imaging enables molecules to be literally flash-frozen  and studied in their pristine natural form without the necessity of using dyes or fixatives.

Several crucial disease causing entities have been studied in this way. Thus the practical uses for the technique are vast. The American Chemical Society president commented that, “This discovery is like the Google Earth for molecules, in that it takes us down to the fine details of atoms within proteins.” The understanding of proteins is important in bioscience as they are ubiquitous in all living entities.

Now that we can actually see the intricate details of the biomolecules in every type of cell, there are no more secrets left!  It can now be understood how the entities involved work in tandem with large cell communities. Apart from being used to unravel the Zika virus, cryo-EM has also been used to capture images of Salmonella’s ‘injection needle’ for attacking cells.

It has also been used to study the proteins involved in the antibiotic resistance and molecular structures governing the circadian rhythm. As far as the Zika virus is concerned, 3D images of the virus at atomic resolution were generated over a few months to enable doctors to start searching for crucial potential targets for drugs. This groundbreaking research won the trio the 2017 Nobel prize in Chemistry.

(The author is with Indian Institute  of Astrophysics, Bengaluru)