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Tuesday, October 3, 2023

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An artist's rendering of Phage.

SDSU Hosts the "Year of the Phage"

Celebrating the 100th anniversary of the discovery of bacteriophage, scientists gathered to reflect on the field's history and speculate its future.
By Michael Price, video by Jeneene Chatowsky

The Curious Aztec takes you behind the scenes of scientific investigation and discovery taking place at San Diego State University.

“Phage” isn’t yet a household scientific term, but it could be someday soon if microbiologists at San Diego State University and beyond manage to get their message out.

Simply put, a phage — short for bacteriophage — is a virus that replicates exclusively inside bacteria. They look a bit like B-movie aliens, with a bulbous head topping a thin stalk and tentacle-like legs dangling below. And understanding them could be the key to developing a new generation of medical treatments that manipulate our body’s bacteria to fight off disease.

This year marks the 100th anniversary of the discovery of phages by British scientist Frederick Twort. In honor of that milestone, SDSU virologists have declared 2015 to be the Year of the Phage, and last week the university hosted a conference celebrating the winding, quirky history and promising future of these enigmatic lifeforms—as well as the equally enigmatic scientists who work with them.

Daring and desperation

Hundreds attended a series of talks by luminaries in the field of phage research. Elizabeth Kutter, a microbiologist at Evergreen State College in Olympia, Washington, began working with phage in 1963 at Cold Spring Harbor in New York. She described some of the very earliest work experimenting with phages to treat diseases. Throughout the 1920s, dozens of phage-based medicines were advertised as treatments for anything you could think of — dysentery, typhoid fever, acute colitis, peritonitis, urinary tract infections and more.

It’s debatable whether many of the medications worked as advertised, but there’s some evidence that at least a few may have been effective. One high-profile case involved movie actor Tom Mix, a star of early Westerns, who contracted peritonitis from a ruptured appendix. His personal physician knew a professor at Stanford University working with phage. The professor arranged for a phage solution to be sent to Mix’s doctor in Los Angeles, who injected it into his patient’s abdominal cavity. Eight days later, the actor was well again.

Kutter provided another example, originally recounted by Stanford microbiologist Gary Schoolnik: In 1948, Schoolnik’s mother was dying of typhoid fever. This was before the advent of antibiotics, and things didn’t look good for her. Desperate, Schoolnik’s father scoured the medical literature and chanced upon an article in the Journal of Bacteriology about a virus that killed the typhoid bacterium. He contacted the article’s author in Los Angeles, and that scientist sent him a phage medication, which he injected into his wife. The next day she was on the road to recovery. “That's real infectious disease experimentation: a mix of science, and daring and desperation,” Kutter said, quoting Schoolnik.

Despite these success stories, there was a distinct mistrust of phage-based therapies among federal regulators and other cell biologists, Kutter explained. A study by the U.S. Food and Drug Administration found that most of these drugs failed to work as advertised. A later report by the American Medical Association found that only phage treatment for staph infections worked reliably.

Modern microbiology

Phage researchers were not deterred by these setbacks, however. The modern era of phage research began in earnest at Cold Spring Harbor, where biologists Jim Watson and Francis Crick had recently puzzled out the structure of DNA and physicist Leo Szilard was wrestling with the consequences of his contributions to the development of nuclear weapons.

It was an era of exploding interest in microbiology, and a motley and eccentric cohort of young biologists, mathematicians and physicists were drawn to studying phages precisely because so little was known about them.

Moselio Schaechter, professor emeritus of biology at SDSU, recalled that as technology improved and scientists were able to decipher more and more about cellular machinery, phage researchers stood at the brink of a microbiological revolution.

“We were immersed in the sense of something being created, something new,” he said.

With so many new tools and techniques available to the researchers, the challenge became deciding which topics to devote time to.

“There was a lot of low-hanging fruit at the time,” Schaechter said. “We had to decide what was worth picking, what questions were important.”

The funding environment was different from today, he added. Money was there for the taking. Nobody was concerned about tenure. At Cold Spring Harbor, you were surrounded by geniuses, and so it was easy tap into the collective ego of the place and charge down bold, risky avenues of research, he said. Some of it even paid off.

“There was a lot of hubris,” Schaechter said, “and the hubris worked beautifully.”

SDSU joins the fray

SDSU emerged as a hub of innovative phage research around 2001 when biologist Anca Segall, formerly director of SDSU’s DNA sequencing facility, recruited a young postdoctoral researcher from the Scripps Institution of Oceanography. His name was Forest Rohwer.

Segall and Rohwer shared a passion for understanding the genetic sequences of phages not cultured in a lab, but sourced from their natural habitat.

“SDSU was one of the first to sequence a marine phage taken from the environment,” Rohwer said. “We were able to figure out how to go into an ecosystem and discover the viruses in it.”

From there, Segall and Rohwer drew other phage-interested scientists to SDSU from a variety of disciplines. They hired computer scientists and mathematicians to bring processing power to bear on viral discovery and sequencing.

“We pulled in more and more people to help us to understand the genomes of phages in different environments,” Segall said.

Today, SDSU is poised to be a major player in the phage-based treatments of tomorrow for diseases and health problems such as obesity, diabetes, and various forms of gut diseases. Segall and Rohwer, along with bioinformatics professor Rob Edwards, direct the Viromics Information Institute, one of the university's Areas of Excellence.

Highlighting the sheer breadth of the interdisciplinary nature of phage work at the university, the phage conference concluded with a phage-centric art exhibition. SDSU students and faculty working with SDSU Arts Alive produced paintings, sketches, sculptures and musical compositions inspired by phages. It was a lively affair, with jazzy, ethereal sounds directed by SDSU music professor Jozefius Waters echoing through the gallery.

Kotaro Nakamura, interim director of SDSU’s School of Art and Design, said that artists and scientists share a curiosity about the world around them. Like many people, he had never heard of bacteriophage before beginning this project, but he was captivated by their visual form and complexity, as well as the passions of the people who study them.

“Scientists and artists, we think in a different language, but our subject matter is the same,” Nakamura said. “We are trying to reflect the world around us.”