The cryo-electron microscope seems like an unwieldy telephone booth. But its ability to create sharp images of proteins is stunning.
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The rise of structural biologyInnovation-minded and partnershipsNew frontiersPublished on 19/12/2022
“When you solve a protein structure, it’s like somebody switches on the light,” says Christian Wiesmann, who heads one of the most advanced microscopy labs in the world on the Novartis Campus in Basel. “If you’re lucky, you can suddenly understand how a whole biological system works,” Wiesmann explains.
Much of his enthusiasm is down to the cryo-electron microscope, or cryo-EM, a Nobel Prize-winning imaging tool, which for laymen may look like an old-fashioned telephone booth with a maze of cables. The high-tech microscope, however, can render high-resolution images of proteins and help researchers better understand these biological building blocks of life whose understanding for medicine is instrumental. Through chemical biology, researchers can then develop custom-built chemical “tools” that fit in the pockets and grooves of protein surfaces – providing biological insights as well as starting points for new drugs.
Together with his team, which includes a handful of scientists from the Novartis Institutes for BioMedical Research, Wiesmann has been focusing on detecting the shape of highly complex and large proteins, an endeavor that, with traditional imaging tools, was considered almost impossible just a few years ago.
“Thanks to the cryo-EM, we now have access to so many important proteins which we couldn’t investigate with other methods. Since we started our facility in 2016, cryo-EM has already contributed greatly to our drug discovery efforts,” says Wiesmann.
A long path
Proteins, which are essential to most biological processes and can be the key cause of a disease if they malfunction, have long been puzzling scientists. For most of the early history of modern medicine, proteins were not even on the radar of drug researchers, who routinely tested the effects of medical compounds in cells, animals and patients, but lacked a molecular understanding of these structures and how they work in the body. Only with the development of X-ray technology, which was discovered around the turn of the 20th century, did scientists gradually learn about the importance of proteins and begin to understand more about their behavior, which allows them to fold in a fraction of a second into structures that are as mysterious as they are beautiful and vital to life on earth.
It took more than 50 years of hard work and a series of Nobel Prize-winning technologies before scientists were able to discern what proteins really look like and what their function is. One of the early breakthroughs was X-ray crystallography, for which researchers Max Perutz and John Kendrew won the Nobel Prize in 1962. The technology allowed scientists to study proteins in a crystalline form to get a sense of their shape and to study their function.
X-ray technology, however, needed years of fine-tuning before researchers could start to catalogue some of the nearly 30000 proteins that exist in the human body alone and the technique has remained fraught with challenges. “I started my professional life learning crystallography, and when I received my Ph.D. in 1996, solving just one crystal structure could take years and was sufficient to earn a Ph.D.,” says Wiesmann. “The biggest challenge is obtaining enough protein and to coerce the protein into forming crystals – and there are numerous examples of proteins that researchers have been trying to crystallize for decades without success.”
