Biophysical Society Bulletin | April 2024

Biophysicist in Profile

Walter Chazin Areas of Research Integrative structural biology in genome maintenance, infec tious disease, and inflammation

Institution Vanderbilt University

At-a-Glance

Walter Chazin , Professor of Biochemistry and Chemistry, the Chancellor’s Chair in Medicine, Director of the Chemical and Physical Biology PhD Program and the Molecular Biophysics Training Program, and the Founding Director of the Center for Structural Biology at Vanderbilt University, has had a prolific career as a researcher and teacher. Now almost 40 years after defending his thesis, Chazin reflects on his journey thus far, including leaving his first attempt at graduate school and swallowing his pride to start again to pursue his dream of becoming a professor.

Walter Chazin

Walter Chazin grew up in New York state, having been born in Lackawanna and moving to Buffalo in his early years and then to the New York City suburbs by the time he was in high school. The second half of his high school career was spent in northwestern Maine. His first serious interest in science be gan in high school, thanks to an engaging chemistry teacher. Chazin’s father had been a union organizer in a steel mill before outside forces pushed him to change careers. “After being called up by the McCarthy Commission, he went back to college to get a second degree and became an analytical chemist,” he shares. “After supporting our family by working in a factory while my father was out of work and reinventing himself as a scientist, my mother went back to college part time to complete her bachelor's of education degree and then worked as a grade-school teacher. Later, she went to grad school, obtained a master’s degree in special education, and worked with students with learning disabilities.” Chazin began his undergraduate studies at Carnegie Mellon University, transferring to McGill University after his freshman year. He completed his bachelor’s degree in chemistry and then took a gap year before beginning graduate studies in chemistry at the University of British Columbia. He left that program after two semesters and took some more time away from academia. “After two-plus more gap years, I returned to graduate school in the Department of Chemistry at Concor dia University in Montreal and obtained my PhD in physical organic chemistry,” he recalls. “I quit my first try at graduate school in the middle of finals in the second semester and received multiple "F" grades. This made it very difficult to get back into a graduate program. After working outside of sci ence for two and a half years, I decided I would do whatever it took to continue pursuing my dream of becoming a professor. To overcome the barrier, I swallowed my pride and accepted the one offer I was able to get, even though it came without a stipend at the start. Fortunately for me, I was married, and the support of my wife was instrumental in making this choice.”

Chazin explains, “My first postdoctoral studies were in Kurt Wuthrich ’s lab at the ETH-Honggerberg in Zurich, Switzer land, at the time that 2D protein NMR [nuclear magnetic resonance] was being developed and the very first protein structures were being determined by NMR. At its root, it was my first postdoc that converted me from NMR in chemistry to applying NMR to study proteins. My primary project in this postdoc eventually led to my research in infectious disease and inflammation; it involved a calcium-binding protein from a family that has several innate immune factors that function in the response to infection both through direct action and by activating inflammatory receptors. I had a short second postdoc with Peter E. Wright at The Scripps Research Institute, where my focus was on further developing practical aspects of protein NMR and applying it to specific proteins.” His transition to becoming an integrative structural biologist, as he now defines himself, began in 1999 when he spent time reflecting on the field as he worked on designing a structur al biology program at Vanderbilt University. “At that point it became apparent to me that to contribute in an impactful way to biomedical research, we had to shift from being defined by our technique to focusing on problems and using whatever tools are needed to solve the problem,” he says. Of his lab's current work, Chazin reveals, “One of our most exciting projects is a by-product of our years of studying the structural biology of the nucleotide excision pathway of DNA repair (NER). The National Cancer Institute has just funded our team to investigate the relationship between mutations in NER genes and the efficacy of standard-of-care treatment of cancer patients with Pt agents. Our team will test the hypothesis that mutations reducing NER sensitize cells to Pt, develop an active machine learning algorithm to predict the effect of NER mutations in tumors, and use structure/ fragment-based molecular discovery to generate a tool com pound for testing the therapeutic value of suppressing NER. A second exciting area of research involves determining the molecular mechanisms that underly the tug of war between

April 2024

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