Graham Hatfull reflected on 25 years of research in a special PNAS paper

In the late 1990s, Graham Hatfull and colleagues reported in the Proceedings of the National Academy of Sciences (PNAS) their findings about genetic connections between distantly related bacteriophages, viruses that kill bacteria, in a paper titled “Evolutionary relationships among diverse bacteriophages and prophages: All the world’s a phage.”

More than 25 years later in 2024, Hatfull was elected to the prestigious National Academy of Sciences and invited to publish a special inaugural paper in PNAS, its peer-reviewed journal. He chose to reflect on the past quarter century of phage research — discoveries, new tools, and breakthrough treatments — but also on the model under which he’s been working.

In his work, Hatfull, who is the Eberly Family Professor of Biotechnology in the Kenneth P. Dietrich School of Arts and Sciences, has not confined himself to a lab surrounded by thousands of frozen phage samples — although he has the phages and the freezers to do so.

Instead, he’s chosen to incorporate an inclusive research education community model with his pioneering Howard Hughes Medical Institute-supported Science Education Alliance Phage Hunters Advancing Genomics Evolutionary Science (SEA-PHAGES) program.

Through the program, students don’t just learn, they support the research endeavor. To date, more than 50,000 students have participated, discovering nearly 30,000 new bacteriophages, and there are surely many more to come.

Hatfull, who was named a Fellow of the Royal Society in 2025, has also leveraged clinical partnerships, using experimental phage-based treatments to successfully treat antibiotic resistant infections. Along the way, Hatfull and collaborators gained new insights into the potential for phage-based treatments. They also uncovered new questions.

Thanks in large part to techniques Hatfull’s lab has developed or contributed to for imaging and genetic engineering of synthetic phage genomes, along with advances in artificial intelligence and increasingly sophisticated biotech tools, he believes the next 10 years of phage research will continue to be fruitful, and that the model he has built can successfully usher in a the next wave of phage research.

Because there is still much to be discovered.

“With a predicted total phage population of 1031 particles or more, dynamically interacting with bacteria at 1023 infections per second, and all happening over perhaps as long as three billion years,” Hatfull wrote, “this has of course produced huge diversity.”

The title of Hatfull’s 2025 paper, “All the world’s a phage,” is a call back to the 1999 paper and a favorite phrase of coauthor and Hatfull’s late colleague, Roger Hendrix.

“The sentiment was more of a prediction at that time as the nature of the phage population was just emerging,” Hatfull wrote. “More than 25 years on, this view of life is on firm footing and, reframing [evolutionary biologist] Theodosius Dobzhansky, nothing makes sense in microbiology except in the light of the phage-bacterium dynamics.”

Photography courtesy of the Royal Society