As part of the Commencement 2026 series celebrating Harvard’s 375th Commencement, Ph.D. candidate Isaac Witte reflects on the “incremental advances” that led to the CRISPR breakthrough. His journey began with a fascination for DNA replication during high school in Overland Park, Kansas, captivated by the complex orchestration of proteins essential for life.<\/p>\n
Witte’s interest was sparked not just by the discovery but by the experiment of Meselson and Stahl, demonstrating DNA’s semiconservative replication. This curiosity propelled him to a research fellowship at the Stowers Institute, where he explored RNA interference, manipulating genetic pathways to observe changes in flatworm regeneration.<\/p>\n
Returning to Berkeley, Witte joined Jennifer Doudna’s lab, drawn to CRISPR’s potential but more intrigued by its natural mechanisms. He explored diverse CRISPR systems, including those targeting RNA and a novel system for diagnostic purposes, which led him to a company aiming to enhance pathogen detection.<\/p>\n
At Harvard, under David Liu’s guidance, Witte investigated phage-assisted continuous evolution (PACE) to tackle gene editing challenges. A naturally occurring CRISPR system, capable of multiple sequence changes without DNA cutting, showed promise for treating genetic disorders.<\/p>\n
Witte and his team faced the challenge of adapting this system for human cells. Through PACE, they identified key proteins to enhance, notably TNSB, which facilitated DNA integration. Their efforts increased the process’s efficiency in human cells over 100-fold, with findings published in Science highlighting its potential to correct complex mutations.<\/p>\n
Despite no single breakthrough moment, Witte emphasized the cumulative effect of incremental improvements. His work could address various genetic diseases, particularly those affecting the liver, though clinical application remains years away. Researchers, including Witte, aim to bridge this gap.<\/p>\n
As Witte continues his scientific journey, he remains committed to exploring new ideas driven by curiosity. “The curiosity-based focus is something I\u2019d like to do long-term as a scientist,” he expressed, acknowledging the role of curiosity and perseverance in achieving major scientific advances.<\/p>\n