University of Oregon researchers have resurrected proteins up to 160 million years old, finding that ancient antimicrobial fragments can outperform modern human versions against drug-resistant bacteria. Described in PLOS Biology, the discovery traces immune defenses to the Jurassic Period to help design next-generation therapeutics.
Scientists Resurrect 160-Million-Year-Old Lactoferrin From Mammal Ancestors
Biologists at the University of Oregon brought prehistoric immune proteins back to the laboratory, tracing the molecular history of life back to the end of the Jurassic Period. The investigation centers on lactoferrin, a vital immune protein present in nearly every body fluid except blood, including breast milk, tears, saliva, snot, and intestinal mucus. About 160 million years ago, the common ancestor of all placental mammals, whose young develop in the womb, emerged, and this defensive molecule appeared alongside it. Titas Sil, a doctoral student in Barber’s lab and lead author of the study published in PLOS Biology on Aug. 25, worked alongside senior author and evolutionary biologist Matt Barber at the UO College of Arts and Sciences to uncover how these natural defenses evolved over deep time.
To rebuild molecules that vanished millions of years ago, the research team compared lactoferrin gene sequences from living species such as humans and cows. Using statistical methods pioneered by Joseph Thornton, a former University of Oregon scientist whose previous lab space is now utilized by the team, Sil executed an advanced ancestral sequence reconstruction. The team synthesized the predicted genes and produced the ancient proteins inside living cells. They then tested the resulting antimicrobial peptides against several stubborn pathogens linked to human disease, including Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Streptococcus.
Extinct Peptides Fight Modern Drug-Resistant Superbugs
Laboratory experiments revealed an evolutionary trajectory when the resurrected peptides faced dangerous superbugs. According to findings funded by the National Institutes of Health, the oldest proteins, dating back roughly 160 million years, successfully attacked bacterial membranes by punching holes in them, but the microbes managed to repair the damage and survive. Peptides reconstructed from more recent mammalian ancestors displayed greater potency.
Some of these more recent extinct variants ultimately outperformed corresponding modern human peptides when pitted against drug-resistant strains. Researchers discovered that a small modification drove this leap in effectiveness. A single amino-acid mutation in the sequence produced an enhancement in the peptide’s ability to rupture harmful cells, demonstrating how minor genetic mutations reshape biological functions over vast stretches of time.
Pathogenic Bacteria Threaten Modern Medicine
This evolutionary excavation addresses a global health crisis as conventional pharmaceuticals lose their punch. Natural defenses like lactoferrin serve a dual purpose: they withhold essential iron to starve invading microbes, and their embedded antimicrobial peptides act as a physical strike force against cell walls.
“For anybody who studies pathogenic bacteria, it’s always in the back of our minds that antibiotics are one of the most important breakthroughs in medicine in the 20th century, but bacteria are, and have been for a long time, evolving resistance to them.”
Matt Barber, senior author and evolutionary biologist at the UO College of Arts and Sciences
Barber noted that looking backward provides a catalog of natural experiments. Evolution is essentially a billions-year-old science experiment, right?
he observed, pointing out that studying what worked and what failed across deep history helps researchers decode nature’s design choices.
Ancient Molecules Build Future Therapeutic Blueprints
While these prehistoric molecules show potency against drug-resistant pathogens, they are not ready to be administered directly as clinical drugs. Researchers emphasize that ancient antimicrobial peptides face structural hurdles, specifically noting that they can be less structurally stable and degrade rapidly in the body. Instead of serving as direct replacements for current medicines, the revived peptides offer blueprints for synthetic engineering.
By understanding the structural modifications that made natural peptides more lethal to pathogens over millions of years, scientists hope to design enhanced therapeutics or combination treatments that outpace bacterial evolution. We’re definitely interested in whether by resurrecting or engineering some enhanced antimicrobial peptides, we could use these as therapeutics down the road,
Barber said.