Introduction and status of cryo-electron microscopy in India

Imagine seeing ribosomes in complex with mRNA, tuberculosis proteins secreting the virulence factors, and so forth. These long unanswered questions are now not only being understood but “seen”. The life and complex machineries associated with it has always perplexed scientists. Cryo-EM or popularly called cryo-electron microscopy now stands as a frontier in structural biology and addressing such crucial questions. The potential and advantage of cryo-EM encompasses seeing the molecule in its natural environment and evading crystallization which is difficult for some proteins. Perhaps not many people would have thought that a technique which initially was synonymic with “Blob-ology” for its blurry low-resolution map would turn out to produce stunning high-resolution maps comparable to established structural biology technique of X-ray crystallography and NMR. The advent of cryo EM and the idea of freezing hydrated biomolecules in its near native state has its own stories of gradual development and experiments. Many crystallographers who were sceptical about this technique later adopted this “resolution revolution” with the introduction of direct electron detectors and image processing software capable of dealing with heterogeneity of macromolecules. It can be said now that cryo-EM has become a normal choice for solving structures of macromolecular complexes and proteins and in many cases is preferred over X-ray crysatallography.

The advent of cryo-EM in India dates to the year 2000. However, the TEM (Transmission Electron Microscope) installed in few institutes were mostly low energy machines which were not capable of attaining near atomic resolution. My PhD supervisor Dr Somnath Dutta produced the first cryo-EM structure of Vibrio cholerae Hemolysin back in 2010 at NICED, Kolkata along with his supervisor Dr Amar Nath Ghosh. The use of high voltage 300kV microscope in India started with its installation at IICB, Kolkata. The invention of direct electron detectors around 2014 dramatically improved image quality and hence attainable resolution.

Raw cryo-EM micrograph of a GroEL protein 50000x magnification, Source: Vossman

With the 2017 noble prize of chemistry being bagged by Jacques Dubochet, Joachim Frank and Richard Henderson for their work in the development of cryo-EM, there is yet another enthusiasm and promise among structural biologist to get deep insight into the fundamental understanding of chemistry of life and explain mechanism by seeing or so-called “visual proteomics”.

With every country throwing crores of investment in procuring high-end cryo-electron microscope, the race to produce better microscopes, excellent DED (direct electron detectors) and delivering it has begun among companies. Despite this fact, procurement, installation and maintenance of cryo-EM is not an easy feat as it seems. The computational requirements and some best high core workstations remain a dreaded target to achieve. Countries like the US, UK and China have managed to procure some of the best high-end cryo-electron microscopes for their research and pharmaceutical industry need. India seems to be a little late in joining the “resolution revolution” but it’s all on the right way. After all, it is said, “The end is where you start from”. India has recently managed to procure state of art 300kV Titan Krios cryo-EM microscope as a part of Bengaluru bio cluster. Soon after, Indian Institute of Science, Bengaluru has acquired 200kV Talos Arctica for imaging the macromolecules. With some of the trained cryo-EM specialist across India, India hopes to see some amazing macromolecular structures and publications arising in the next decade. There are several trained cryo-EM practitioners in India, who have received formal training in cryo-EM technique. Proper training and dissemination of knowledge of this technique are crucial to fully utilize the potential of this technique. There have been some recent efforts in this direction in the form of Conferences and workshops to train students and some faculties to carry out cryo-EM in their labs. India is all set for the exciting ride of cryo-EM!!

Haaris Ahsan Safdari

Haaris Ahsan Safdari is a PhD student at Indian Institute of Science at Molecular Bio-Physics Unit.


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