An $8 million investment into a cutting-edge microscope at West Campus promises to yield advances in the field of structural biology.

As a tool to study the atomic and molecular structures of complex biological molecules, the cryo-electron microscope offers researchers the ability to determine the structures of previously unmapped macromolecules. The Titan Krios cryo-electron microscope arrived at West Campus in January, was dedicated in June and officially opened for use in September.

“Cryo-electron microscopy is a technology that’s taking the structural biology world by storm, and for Yale to continue to be a world leader in structural biology, it’s important to make this investment,” said Scott Strobel, vice president for West Campus planning and program development.

Cryo-electron microscopy builds upon the technique of X-ray crystallography, which can determine the structure of a crystallized protein by seeing how it diffracts X-ray beams. Cryo-electron microscopy, however, blasts electrons, rather than X-ray beams, to capture images of the desired molecules.

According to West Campus scientist Shenping Wu, who runs the new Krios facility, this technique allows researchers to study dynamic complexes that resist crystallization or do not diffract X-rays well — characteristics that have historically hindered research in structural biology.

These molecules include membrane proteins, an area studied by Frederick Sigworth, a professor in the School of Medicine and School of Engineering & Applied Science. Membrane proteins — which include cellular receptors, ion channels and transporters — are difficult to crystallize because they have to be taken out of the natural cell membrane and placed in a caustic detergent, Sigworth explained.

“The development of cryo-electron microscopy has just given us an explosion of membrane protein structures,” said Sigworth, who is currently studying voltage-gated ion channels. His team has just used cryo-electron microscopy to develop the structure of these channels — matching the crystal structure previously obtained by X-ray crystallography. Next, Sigworth said, he will use cryo-electron microscopy to provide new insight into the mechanisms of ion channels.

The $8 million investment is an important step in the push by University President Peter Salovey to improve the sciences at Yale, according to Sigworth.

Bringing cryo-electron microscopy to Yale reflects the institution’s commitment to research and to the ongoing strength of Yale in the structural studies of macromolecules, Strobel said. He added that the new cryo-electron microscopy instrument offers an additional advantage to the University’s science mission in its faculty recruitment efforts.

This technology is critical to bringing leaders in structural biology research to Yale, he said, and these efforts have already come to fruition for the departments of Microbial Pathogenesis and of Molecular Biophysics & Biochemistry. The departments recently hired professors Jun Liu and Candice Paulsen, respectively, both of whom use cryo-electron microscopy in their research.

“Yale is one of the strongest institutions in the field of cell biology, and Yale has invested in this technique to potentially revolutionize structural biology and cell biology,” Liu said.

One key area of focus in Liu’s research is assembly of flagella, structures that allow bacteria to move. Cryo-electron microscopy is particularly helpful because taking the proteins involved out of their natural environment — which is required in X-ray crystallography — may alter their interactions and make-up, he said.

Because the microscope is more than 12 feet tall and requires solid bedrock underneath, West Campus offered a prime location to house the Krios facility, according to Strobel. He noted, however, that the instrument is expected to be moved in a few years to the new Yale Science Building on Science Hill — set for completion in 2019.

The fact that eight cryo-electron microscopy microscopes were introduced to institutions around New England in the past two years demonstrates the advances being made in the structural biology field, Liu said.

“I keep having to pinch myself and saying, ‘This actually works.’” Sigworth said. “There’s a lot of ‘magic’ in the amazing algorithms that process the huge amounts of image data.”

This year’s Nobel Prize in chemistry was awarded to Jacques Dubochet, Joachim Frank and Richard Henderson for developing the technique of cryo-electron microscopy.

Amy Xiong |