Kirchdoerfer joins department, campus virology community to utilize cryo-EM technologies

Photo of Robert Kirchdoerfer
Assistant professor Robert Kirchdoerfer.

When Robert Kirchdoerfer was offered a faculty position in the University of Wisconsin–Madison Department of Biochemistry, it was a bit of a homecoming. The 2006 undergraduate alumnus and Oregon, Wisc. native will be arriving back on campus in mid-August — this time as an assistant professor in Biochemistry and the Institute for Molecular Virology.

Following his Bachelor of Science with majors in biochemistry and genetics, Kirchdoerfer earned his Ph.D. in biophysics at Scripps Research Institute in Southern California and continued there as a postdoctoral scholar before coming back to UW–Madison. During graduate school he became fascinated by viruses while working on the flu virus and it’s an interest that guides his research today.

“Viruses are so fascinating to study because they defy expectations,” he explains. “For every rule and trend in biology, there is a virus out there that somehow breaks it. This means that viruses have a lot to teach us about what biological systems are capable of.”

His position in the Institute for Molecular Virology is part of its recent Metastructures of Viral Infection cluster hire initiative, supported by the Office of the Provost. The cluster is creating three new positions in total to leverage and improve UW–Madison’s current strengths in RNA virology, DNA virus epigenetics, and atomic-level imaging, and expand the institute’s research portfolio into the evolving field of metastructural virology. UW–Madison’s Cluster Hiring Initiative was launched in 1998 as an innovative partnership between the university, state and the Wisconsin Alumni Research Foundation (WARF).

Image of a biological complex. Particle appears suspended in space, with different colors representing different parts of the complex.
The structure of the SARS-CoV nsp12 polymerase complex. Being able to visualize the structure of viruses and their parts is an important step in finding vaccines and antivirals. Image courtesy of Robert Kirchdoerfer.

We are looking to bring young virus talent like Robert to campus and he will be a great addition as part of this cluster,” says biochemistry and molecular virology professor Ann Palmenberg, who is leading the cluster. “Many of us in the virology community already on campus are extremely excited about having cryo-EM capabilities and having Robert in this role will be critical.”

In his role, Kirchdoerfer will play a key part in bridging the virology community to the newly established UW–Madison Cryo-EM Research Center, directed by biochemistry professor Elizabeth Wright. Using cryo-electron microscopy (cryo-EM) technology allows him and other virologists to get an extremely detailed look at viruses and how they work, which is an important piece of the puzzle when exploring therapies and vaccines.

“One of the most straightforward ways of figuring out how something works is by looking at it,” he says. “My research uses structural biology methods like cryo-electron microscopy and X-ray crystallography combined with more traditional biochemistry approaches to examine the protein machines of viruses in incredible detail. By viewing how these viral machines are put together and function, we can identify vulnerable points in the virus where we can intervene with new vaccines and antiviral drugs. Bringing high-resolution cryo-EM to bear on important questions in virology builds on UW–Madison’s existing strengths in structural biology and virology.”

In order to infect a host, viruses must follow several steps, including binding to the host cell, entering it, and then replicating their genetic material, either RNA or DNA. Each of these stages offers possibilities for intervention to shut down infection, and Kirchdoerfer and his lab will study each of them.

Specifically, Kirchdoerfer studies coronaviruses, a common type of virus. Most are not harmful and some cause mild flu-like symptoms. However, some are more dangerous, especially, he says, those that jump between animal species and find their way into humans.

“Viruses like SARS-CoV and MERS-CoV both originated in bats before eventually moving into humans,” he explains. “Infection with these highly pathogenic human coronaviruses can lead to a severe and sometimes fatal respiratory disease. Developing vaccines and treatment strategies will help the world prepare for the next coronavirus outbreak.”

His work in vaccines and antivirals doesn’t stop with humans. He explains that since coronaviruses affect a large variety of animal species — many kept as pets or important agricultural livestock — the research has broad potential to aid human, animal, and economic wellbeing by preventing or battling outbreaks.

For experiments in cryo-EM, samples must be frozen to extremely cold temperatures to stop the molecules from moving and then electron beams are shot at the frozen molecules in the microscope to capture an image of its structure.

When electrons hit the biological sample in the microscope, they scatter and then pass through a series of lenses to generate an image. In single particle cryo-EM, which is often used on protein complexes, hundreds of thousands of such images in random orientations are combined in the computer to reconstruct the molecular structure.

“Single-particle cryo-electron microscopy is like playing shadow puppets with proteins and electrons,” Kirchdoerfer says. “If I were to take lots of pictures of an object in random orientations and look only at the shadows, I can reconstruct a 3-dimensional representation of a the object.”

Kirchdoerfer says he is glad to be back on campus and able to once again stroll by the lake and through Allen Centennial Gardens, as well as indulge his sweet tooth with Babcock ice cream.

“I’m very excited to be back at UW–Madison,” he says. “I had a fantastic experience on campus as an undergraduate and I’m looking forward to contributing to this amazing community of faculty and students. The strong virology community and developing cryo-electron microscopy resources make UW–Madison an ideal fit for my research program.”