Remembering Bill Scott (1963-2025)

We are deeply saddened to report that the RNA and structural biology fields have lost one of their most brilliant scientists. Bill Scott died on October 8th from a rapidly metastasizing melanoma. Apart from his ground-breaking research on the molecular structures and mechanisms of catalytic RNAs, Bill is widely regarded as a hero by structural biologists throughout the world for his generous efforts in making it possible for them to solve and refine complex molecular structures on their laptops.

William G. Scott was born in Evanston, Illinois to Dorothy and William J. Scott. He is survived by his wife Sara O’Rourke, their children William, Anna-Marie and Michael and his sister Lisa Peterson. Bill inherited an intense sense of social justice both from his father (who was Attorney General for the State of Illinois) and during his graduate years at Berkeley.

After taking his undergraduate degree in chemistry and biology from Bates College, Bill went on to do his graduate work in crystallography at UC Berkeley where his thesis adviser Sung-Hou Kim agreed to let him attempt to solve the structure of the then newly discovered hammerhead ribozyme. After conceding initial defeat on the hammerhead, he solved the crystal structure of the aspartate receptor, receiving his Ph.D. in Biophysical Chemistry in 1992. He then went to the MRC Laboratory in Cambridge for postdoctoral research with Nobel laureate Aaron Klug, whom he persuaded to let him continue to pursue the hammerhead structure, work that was honored with the Max Perutz Outstanding Young Scientist Award in 1996. Bill’s first academic appointment was as Assistant Professor of Chemistry at Indiana University, finally joining the Department of Chemistry and Biochemistry and the Center for Molecular Biology of RNA at UC Santa Cruz in 1998, where he spent the rest of his career.

One of Bill’s prevailing passions was the RNA World hypothesis and the role of RNA in the origin of life, which motivated much of his excitement about the structure and function of ribozymes. The centerpiece of his many scientific interests continued to be the hammerhead ribozyme, beginning with the crystal structure of a minimal hammerhead enzyme (1) and its transition state intermediates (2,3). Although the minimal hammerhead was able to catalyze site-specific RNA cleavage, it was 1000-fold less active than the full-length ribozyme. Nevertheless, its structures provided crucial insights into its mechanism of action.

Everything changed in 2006, when the Scott lab obtained a 2.2 Å crystal structure of a full-length Schistosoma mansoni hammerhead ribozyme, which revealed tertiary interactions occurring remotely from the active site that were absent from the minimal construct (4). Comparison with other full-length hammerhead sequences revealed a maze of idiosyncratic variations, but Bill was able to identify a tertiary Hoogsteen A-U pair that appeared to be conserved in all full-length sequences. Together with his wife, the virologist Sara O’Rourke, they tested this possibility and discovered that the catalytic power of the full-length hammerhead could be mimicked simply by introducing this single Hoogsteen A-U tertiary base pair into a minimal hammerhead (5). This discovery resolved what had appeared to be irreconcilable differences between mechanistic crystallography and solution studies in unpublished work, they went on to develop an ingenious scheme to create designer hammerhead ribozymes that recognize and cleave RNAs of any target sequence. They even used this strategy to cleave specific RNA sequences in the spike protein region of the coronavirus genome as a potential therapeutic to address the COVID-19 epidemic.

Bill was, moreover, a gifted teacher and lecturer, inspiring a generation of young biochemistry students while keeping them in stitches with his wry sense of humor. He was a most stimulating and supportive colleague, always generous with his time and with his formidable expertise and original ideas. He will be greatly missed by RNA researchers, structural biologists and passionate, thinking human beings everywhere.

Bill’s last wish was “no flowers or fuss”, but requested that people make donations to the Middle East Children’s Alliance for assistance to the children of GAZA

-Harry Noller