Gene transfer agents: How bacteria have tamed their greatest enemy

Since the dawn of life, a relentless battle has raged between bacteria and bacteria-infecting viruses known as bacteriophages (or simply, “phages”). These primitive adversaries have fundamentally opposing goals. While bacteria seek to survive and reproduce, phages aim to hijack a bacterial cell’s inner machinery to replicate their own genes — killing the cell in the process. Despite this, biologists generally agree both sides exist in a delicate stalemate with no clear “winner.” They note that bacteria continually evolve new ways to detect and destroy viruses, while phages constantly develop strategies to evade this detection. 

However, a growing body of research demonstrates this might not always be true. Evidence indicates that many bacteria successfully domesticated phage invaders, turning them into “selfless viruses” that deliver beneficial DNA to neighboring cells. Named gene transfer agents (GTAs), these phage derivatives challenge our understanding of basic virology and bacterial genetics.

“Since the dawn of life, a relentless battle has raged between bacteria and bacteria-infecting viruses known as bacteriophages.”

Initial evidence for GTAs was discovered in 1974 when researchers at the Saint Louis University School of Medicine noticed that cells of the species Rhodobacter capsulatus could share antibiotic-resistance genes without making physical contact. Further investigations revealed these cells transported DNA to neighbors in a protective carrier, similar to the protein coat of a virus, yet smaller than any known bacteriophage. A second team visualized these carriers under an electron microscope and found particles resembling miniaturized versions of bacteriophages bursting from a few lysing cells. As these particles did not promote lysis in their recipients, they theorized that a defective phage unable to hijack cells could have integrated its genome into a Rhodobacter ancestor. Over generations, subsequent cells learned to exploit these viral genes to share DNA with the community at the cost of the individual. While it was an intriguing premise, biologists struggled to address this hypothesis without modern bioinformatic tools. As a result, GTAs remained largely unexplored for decades.

However, with 21st-century advancements in computational biology, GTA research has accelerated. Since their discovery, biologists have identified similar systems across diverse bacterial and archaeal genomes. Notably, these GTAs all resemble different ancestral phages, suggesting prokaryotes have independently domesticated viruses throughout history. Building on this, a team from Dartmouth College used machine learning to analyze over 1,400 genomes of species related to R. capsulatus and found that around 58% had regions strongly resembling known GTA systems. This points to phage domestication being more widespread than previously thought and potentially a key driver of bacterial genetic exchange.

In addition to computational data, recent experiments further support the “selfless virus” hypothesis. Extracting and sequencing DNA from GTAs reveals they randomly collect genetic material from across the bacterial chromosome rather than preferentially select viral genes. Further analysis also reveals that GTA bodies are too small to fit every ancestral viral gene needed for self-replication in another cell — preventing infection. Finally, studies demonstrate that GTA production maximizes when cells reach peak density and become stressed due to nutrient depletion. This may explain why many species have adopted and maintained GTA systems. Although GTAs are fatal to individuals when expressed, they may benefit the larger community under stress by supplying DNA that could introduce new alleles or raw material for repairing chromosomal breaks. Supporting this idea, Dr. Kevin Gozzi and Dr. Michael Laub at MIT recently demonstrated that GTAs released from cells under radiation stress supplied DNA templates to their neighbors and allowed them to replace damaged genes.

GTAs have long been a mystery in microbiology that scientists are only beginning to unravel. Many questions remain, such as what factors promote a cell to self-sacrifice for the public good rather than relying on GTAs from another. It is also unclear whether similar viral domestications have occurred in eukaryotes. Ongoing research on GTAs hopes to answer these questions, further untangling the complex relationship between viruses and cellular life. According to Dr. Gozzi, “Figuring out how bacteria and viruses cooperate can reshape our understanding of how the microbial world evolves.”