Atlas of the Cell

A new exploration has begun. Not around the globe or towards distant galaxies, but into the living cell by way of the world’s most advanced electron microscopes. Delta met with two of the initiators of the Netherlands Centre for Electron Nanoscopy (NeCEN): Professors Peter Peters and Henny Zandbergen.

Interaction between proteins - Max Planck Institut of Biochemistry

With its steel side panels towering meters above one’s head, the colossus Titan is an impressive machine. The steel giant measuring 1.5 meters long and wide, and four meters high is an electron microscope, able to perceive details of atomic size.

Two weeks ago news broke that the Netherlands Centre for Nanoscopy (Necen) in Leiden, an alliance of ten universities and institutions including the universities of Leiden, Rotterdam and Delft, was allocated 6 million euro’s for their first microscope – something similar to the Titan in the Van Leeuwenhoek laboratory. The microscope was the first item out of a package totalling 38 million euro’s for a centre specialised in molecular biological imaging. But that was before the crisis broke.

“We’re on the start of a booming business”, says Professor Peter Peters. “The number of publications on biological imaging in major science magazines as Science, Nature or Cell increases exponentially.” Peters is part-time Professor in Delft at the faculty of Applied Sciences and Professor at the Dutch Cancer Institute (NKI) in Amsterdam.

“In the last few years, the idea that a cell was just a bag of protoplasm with a nucleus has made way for a whole new view of the cell. We now see the living cell as a tiny universe in which proteins collaborate and form hundreds of different macromolecular machines, all with their own specialised task”, Peters explains. And since the function of a protein (a large molecule, assembled from typically hundreds of amino acids) depends mainly on its three dimensional shape, transmission electron microscopes are deployed on a large scale to scan all parts and particles in the cell at atomic resolution and in three dimensions. Ultimately, the effort should produce an atlas of the cell, showing each and every detail and its relationship to the rest. “We won’t be doing that on our own”, says Professor Henny Zandbergen, an electron microscope specialist at Applied Sciences, “we will join a network of about fifteen groups worldwide working in this field.”

The idea of imaging proteins dates back to the 1970’s, but in practice it proved difficult to scan biological material without damaging it with the electron beam. “It turned into a amorphous mess”, Zandbergen says.

What has changed in the mean time is the consequence of several instrumental improvements, including a much higher sensitivity of the detectors and highly sophisticated image reconstruction techniques.

A cell will now be ‘quench frozen’, which means it will be frozen at – 150 Celsius so fast that water inside the cell won’t have time to form (damaging) crystals. The sample will be kept at cryogenic conditions as a diamond knife cuts it into slices measuring only tens of nanometres. The microscope can automatically record the electron transmissions of the about 160 slices, which will be reconstructed into a full three dimensional tomography of the cell.

Another technique called ‘single particle analysis’ can be applied to obtain high-resolution 3D-images of proteins. From a smear of ten million molecules the system can automatically recover the molecular structure.

The first specialised electron microscope (or ‘nanoscope’) will be installed in the Gorleaus Laboratory of the Leiden University after the summer. The organisation hopes for second one early next year, courtesy of the European Fund for Regional Development, the province and municipalities.  The crisis has forced the initiators to look beyond the Dutch funding on large-scale infrastructures. Eventually Peters wants Necen to become an independent institute with it’s own building, just like the NKI. It will be open to all participants as well as to biotech companies renting ‘beam time’.  Based on the rise of publications on structural molecular biology, Peters expects the centre to expand due to the rising demand. “Just like we don’t think one telephone per village is enough anymore, or just two cars for the mayor and the police.”