Beyond the electron cryo-microscope

15 December 2018
Nobel prize winner Richard Henderson on structural biology and scientific collaboration

Our recently opened ‘VIB-VUB facility for Bio Electron Cryogenic Microscopy’ (BECM) hosts the newest kind of JEOL electron cryogenic microscope, one of just three in the world. The guest of honor at the inauguration was none other than one of the brains behind this technology: Richard Henderson, from the Medical Research Council Laboratory of Molecular Biology in Cambridge (UK).

In 2017, structural biologists Richard Henderson, Jacques Dubochet and Joachim Frank were awarded the Nobel Prize in Chemistry. Their contributions enabled the development of electron cryogenic microscopy (cryo-EM) for the high-resolution structural determination of biomolecules in solution: a breakthrough in the field of structural biology.

Universities as well as biotech companies are lining up to make use of this new microscope. What is so groundbreaking about the device?
Richard: “For about 50 years, scientists have been trying to determine the structures of proteins in the human body. Knowing exactly where each atom is located enables us to better understand diseases and develop drugs to treat them. However, our knowledge of human protein structures currently extends to a fraction of these.

Since 1995, we’ve mainly made use of X-ray crystallography to determine the atomic structure of proteins. But the problem with crystallography is that it can only be applied to proteins that have been crystallized. This is not always possible and often takes years, whereas cryo-EM leads to results quickly and can be used to examine any protein. In principle, there are no conditions and no limits to the type of specimen the technique can analyze.”

What triggered you to explore the field of cryo-EM?
Richard: “In 1993, I was personally invited to attend a meeting in the French city of Grenoble. The European Synchrotron Radiation Facility (ESRF) was just about to open, and some researchers were planning to build an X-ray microscope at the site. Since I was already aware of the disadvantages of X-rays and the benefits of electrons for microscopy at that time, I was determined to convince all 50 other attendees that their plans were flawed. However, I didn’t succeed.

That’s when I decided to bring clarity to everyone who was lacking profound knowledge on the two methods. I started writing a review, and while I was doing so, I got more and more into the subject. Finally, my calculations proved that electron microscopy works a thousand times better than X-ray microscopy when analyzed in terms of the amount of information that can be obtained for a fixed amount of radiation damage to the specimen. From then on, I couldn’t have been more optimistic about further investigating the opportunities of cryo-EM.”

How did the relationship between X-ray and cryo-EM researchers develop from then on?
Richard: “X-ray researchers used to think of us in a derogatory way, and vice versa. However, they’ve
now all switched to electron microscopy. Five years ago, only 1/100th of all known protein structures were being detected via electron microscopy. By joining forces, that ratio has now been reduced to 1/10th, and has even reached parity for membrane proteins.”

How important are collaborations like this within the scientific community?
Richard: “They’re becoming ever more important. Take, for example, the history of authorship of scientific articles. For years, they would have had one or two authors, max. Contributions from 20 authors aren’t exceptional today. The reason for this is that science has become more technically demanding. In structural biology, we need researchers with expertise in molecular biology, genetic manipulation, protein purification,
sample preparation, electron microscopy and computing.

So, it should come as no surprise that the most successful institutions are those in which people are encouraged to have a chat. That could be in the restaurant or canteen, during lunch or over tea time. By analyzing and reflecting on a topic in group setting, researchers may discover that a certain experiment isn’t worth their time. Chance meetings can really work wonders.”

There’s still plenty of competition in the scientific world. How does this affect possible collaborations?
Richard: “Sometimes it affects collaborations in a negative way, but competition can be a good thing, too. It makes people work harder. Patents were even invented to encourage scientists and investors to put all their energy and money into research – without worrying about someone observing from a distance and waiting to steal their idea.”

Installing the electron cryo-microscope required an investment of 4 million euros. Will the device remain as expensive and exclusive as it is today?
Richard: “We desperately want to ‘democratize’ the microscope in the future. This means we’ll try to render it as simple and accessible as possible. It might develop in the same way as DNA sequencing, which emerged in 1975 and was really unique back then. Today, we can simply send DNA via mail and receive the sequence by email the next day. I hope the same will happen to protein structures in the future.”

So, is improving cryo-EM next on your scientific bucket list?
Richard: “Yes, definitely. We knew cryo-EM was going to be good, but there’s still a lot of work to be done in the field. Once the cryo-EM field is fully established, I might – considering my background in physics – become an enthusiastic follower of other novel research directions. I especially admire the recent spectacular progress in gravitational wave observations. So, I won’t be idle!”

“The most successful institutions are those in which people are encouraged to have a chat. Chance meetings can really work wonders.”- Richard Henderson

---
Opening a new research era
The microscope in the ‘VIB-VUB facility for Bio Electron Cryogenic Microscopy’ (BECM) is unique in Europe and was installed thanks to a four-million-euro grant from Research Foundation - Flanders (FWO). It allows images of the building blocks of the human body to be produced with atomic precision. The device is so unique that other universities as well as biotech companies are lining up to use it for measurement purposes. The new microscope will be run as a multi-user facility under the expert supervision of Rouslan Efremov (VIB-VUB Center for Structural Biology).

Rouslan: “The JEOL cryoARM300 is the tool that allows three dimensional structures of proteins to be solved without need of crystallizing them. This microscope will significantly facilitate and accelerate many biological projects that require knowledge of the structures of proteins, protein-protein and protein-ligand complexes with atomic-resolution precision. We believe that it will have a significant
impact on the biological research performed at VIB in Flanders and beyond.”

The 4 meter high microscope is housed in the former student housing complex, at a central location
on the VUB Campus in Etterbeek. The modernistconcrete modules were built in the nineteenseventies
by architect Willy Van Der Meeren.


Rouslan Efremov, Jan Steyaert and Han Remaut​
©Saskia Vanderstichele-VUB​



Richard Henderson and Rouslan Efremow​
©Maxime Taillez