Joachim Frank says he has always been good at seeing patterns. That skill was critical to his work that was honored with a 2017 Nobel Prize in Chemistry. Frank shares the award with Jacques Dubochet and Richard Henderson for contributions to developing cryoelectron microscopy (cryoEM). The method is increasingly popular—including among drug designers—for visualizing biological molecules and complexes in their natural state. Recent technical advances mean that viruses, antibody-antigen complexes, and internal components of cells can be modeled in great detail and high resolution using cryoEM data. 

Frank has been a professor at Columbia University in New York since 2008. However, he did much of his early cryoEM work when he was at the New York State Department of Health and State University of New York at Albany, which is when Poul Nissen first met him. Nissen is a professor in the Department of Molecular Biology and Genetics at Aarhus University, the site of one of the Nordic region’s cryoEM facilities. 

Nissen says that recognizing cryoEM with a Nobel Prize is “absolutely fantastic” and that Henderson, Dubochet, and Frank are worthy recipients. In the network of cryoEM facilities in Aarhus, Copenhagen, Umeå and Stockholm, Nissen says, “We’ve been working on bringing more attention to cryoEM, so we’re thrilled about the Nobel Prize.”

A natural at pattern detection 

Frank was born in Germany and educated and trained in Germany, the United States, and the United Kingdom. Like his co-awardees Henderson and Dubochet, Frank has a physics background. His contribution to cryoEM was developing the analytic methods for generating high-quality, three-dimensional molecular models using many low-resolution two-dimensional electron microscope images taken from different angles. 

Data analysis for single-particle cryoEM, the method that is mentioned most in Nobel news, is complicated because the imaged molecules lie in random orientations. The method Frank and colleagues developed sorts many low-quality images of single molecules by their orientation. It then averages data for the different orientations to get a 360-degree structural model.

CryoEM can be used with mixed samples in which the molecules are in a variety of forms with different conformations or modifications. The ability of cryoEM to image heterogeneous mixtures lies behind some of Frank’s most well-known work. Because cryoEM catches and traps biomolecules or complexes in the act of performing a function and interacting with other molecules, it can show the conformation of an enzyme or complex at all stages of a process. In his phone interview with Adam Smith for Nobel.org on the day of the Nobel announcement, Frank described this phenomenon as molecules “frozen in the process of doing their thing.” 

Frank and colleagues used cryoEM to model the conformations that ribosomes go through as they synthesize proteins. As Frank described it in his interview with Smith, “We have a whole inventory of the molecular machine in its various states, and then we can connect them in some kind of a narrative.” The narrative images that Frank’s group produced of ribosomes going through their work cycle are so striking that many scientists remember where they were when they first saw them.

Like many structural biologists, Nissen says, Frank is good at looking at blurry electron microscopy images and “clearing away the fog and seeing how they fit together” to reveal a molecule’s configuration. Nissen began collaborating with Frank in the late 1990s on proteins that interact with and regulate ribosomes. The first project their groups worked on together used cryoEM to establish the protein RACK1 as a multifunctional, ribosomal regulatory component. 

Nissen praises Frank as a collaborator for his high standards. “He’s strict and thorough about his work,” Nissen says. “He’s stubborn, in a good sense. I had no doubt that our structures were very high quality. He’s blunt and honest about his opinions but fun and very good company, so it’s easy to have discussions with him.”

In addition to being a renowned biophysicist, Frank is a writer and a photographer. Those creative talents permeate his science, especially the presentation of his research, which always has compelling figures and illustrations. “He’s very thoughtful about how he disseminates his work, including in talks and classes, and has a good aesthetic sense,” Nissen says. “He sets the standards for conveying cryoEM results.”

A tool for dynamic biological analyses

CryoEM is just one of many methods for solving biological structures, along with x-ray crystallography, mass spectrometry, nuclear magnetic resonance (NMR) and other techniques. In his 2007 Inaugural Article on the occasion of his election to the U.S. National Academy of Sciences, Frank acknowledges the contributions of x-ray crystallography to figuring out the cycles that ribosomes go through as they connect amino acids into proteins. In a 2016 paper, he notes that single-molecule fluorescence resonance energy transfer (smFRET) is a perfect complement to cryoEM for gaining details about the dynamic process of ribosomal protein synthesis. SmFRET measures distances between molecules by detecting how the transfer of energy from one to another affects attached fluorescent probes.

All these tools are now available to life scientists, whether they are studying basic cell biology or structure-based drug design for a biotech or pharmaceutical company. The Nordic network of cryoEM facilities means this method will be increasingly accessible to the region’s researchers. “If you want to interfere with protein-protein interactions or map antibody-binding sites or binding sites for small molecules that could be drug leads, cryoEM is very helpful,” Nissen says. “It definitely has important life science applications and will lead to a lot of discoveries that could launch startup activities.”