Paleoproteomics Pushes Beyond the Limits of Ancient DNA
Ancient proteins are helping scientists study evolution far beyond the preservation limits of DNA.
For many years, ancient DNA has been the gold standard for understanding the past, helping reconstruct extinct species, ancient migrations, and the evolutionary history of humanity itself.
However, DNA has limits. Outside cold environments, it degrades quickly, often disappearing entirely after a few hundred thousand years, leaving much of history molecularly silent.
But proteins may be changing that.
Through paleoproteomics, the analysis of ancient proteins, researchers are starting to uncover biological information from samples considered beyond molecular reach.
At the center of this growing field are researchers such as Dr. Enrico Cappellini, professor at the University of Copenhagen, and Dr. Alexandra Morton-Hayward, a postdoctoral researcher at the University of Oxford. Cappellini pioneered the recovery of ancient proteins from dental enamel, helping establish paleoproteomics as a tool for deep-time evolutionary research, while Morton-Hayward currently focuses on the preservation and analysis of ancient soft tissues, including fossilized human brains.
Technology Networks spoke with Cappellini and Morton-Hayward to discuss how paleoproteomics is changing evolutionary biology, the technical hurdles still facing the field, and why proteins may reveal aspects of ancient life that DNA cannot.
What is paleoproteomics?
Proteins are the molecular machinery of life. Built from chains of amino acids encoded by DNA, they form tissues, regulate metabolism, and carry out nearly every biological process in the body. Unlike DNA, some proteins can persist long after death, particularly when trapped within mineralized tissues such as bone, dentine, and dental enamel.
“DNA, or someone's genotype, is like the Encyclopedia Britannica; it tells you all that you could want to know about the world,” said Morton-Hayward. “Whereas proteins are more like a daily newspaper, they tell you what's happening in that world today.”
Ancient DNA can reveal evolutionary relationships and inherited traits, but proteins may provide a closer link to phenotype, physiology, and lived biology.
“It's like DNA tells you the potential, but proteins tell you the realized biological function—so how someone might have looked and where they were placed on the tree of life, vs proteins telling you what their life was like, which is an amazing glimpse into the past,” Morton-Hayward added.
“With protein analysis, we can recover genetic information that goes farther back in time than the limits of DNA preservation. So, with ancient proteins, we can obtain genetic information from those that are too old or too degraded for recovery of ancient DNA,” explained Cappellini.
The analytical workflow behind paleoproteomics combines chemistry, molecular biology, and high-resolution instrumentation. Technically, paleoproteomics relies on a series of sophisticated methods:
- Extraction of preserved proteins from fossil material
- Analysis via tandem mass spectrometry (MS)
- Reconstruction of amino acid sequences and post‑translational modifications
“One of the methodological developments was something that I introduced a while ago, which was the extraction of million years old proteins from dental enamel—the outer material of the tooth crown, and it is the hardest material in vertebrates,” said Cappellini. “I was the first one to show that it was possible to do this from material that old.”
Together, these approaches are taking fossils from static anatomical remains into molecular datasets capable of revealing evolutionary relationships, physiology, and behavior.
What ancient proteins reveal about evolution
The impact of paleoproteomics is already being felt across evolutionary biology.
One example involved Homo antecessor, a hominin species discovered in Spain and dated to ~800,000 years ago. Preserving DNA from that age and environment is effectively impossible, but enamel proteins allowed Cappellini and his team to analyze its evolutionary relationships directly.
“We retrieved proteins from hominin fossil samples, so from species that are our close relatives, but not necessarily on our evolutionary line,” said Cappellini.
Recent studies have since demonstrated how paleoproteomics can clarify the placement of extinct hominins within the human family tree, filling gaps left by morphology alone.
The field has also pushed beyond human evolution. In 2019, Cappellini recovered enamel proteins from a 1.77-million-year-old rhinoceros fossil from Dmanisi, Georgia—at the time the oldest genetic information ever retrieved from a mammal.
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More recently, Cappellini and colleagues extended the timeline even further.
“About a year ago, we were able to show that it's possible to recover proteins that are 10s of millions of years old,” he said. “This was using material from a fossil rhino ~20–25 million years old.”
The findings allow researchers to understand the diversification of mammals following the extinction of non-avian dinosaurs 66 million years ago.
“It's not just the reconstruction of human evolution, but also the reconstruction of the evolution of older species, way beyond what DNA can do,” Cappellini added.
Paleoproteomics beyond bones and teeth
Yet some of the field’s most intriguing possibilities may come not from teeth or bones, but from soft tissues.
“In archaeology, we're usually working with bone and enamel because they're highly mineralized,” Morton-Hayward explained. “But biologically, bone is relatively inert metabolically—and in terms of proteomics, the bone expresses less than 9% of all human proteins.”
Soft tissues tell a richer biological story.
“Internal organs like the brain, the liver, the lungs, the gut, the kidneys—they are much more interesting,” she said. “The brain, for instance, expresses ~75% of all human proteins, and those proteins are really diverse. They reflect immune status, metabolic activity, and regulatory activity, so there's a much closer link to phenotype and physiology with soft tissue proteins than with bone and enamel.”
“We can learn a lot from bones and teeth, but it's just an order of magnitude more illuminating when you move to the soft tissues,” she added.
Historically, preserved soft tissues have often been treated as exceptional curiosities rather than systematic research resources. Morton-Hayward argues that the mindset is changing.
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“Every time a new brain is found preserved, it's described as an exceptionally rare and unique phenomenon,” she said. “But there are more than 4400 brains preserved across the world, found or reported over the last 400 years. At what point do we stop describing these things as unique?”
Studying soft tissue proteins, however, presents technical challenges. Unlike enamel or bone, soft tissues are not mineral-bound and therefore require entirely different extraction strategies.
“We tested 10 different protocols,” Morton-Hayward said. “We needed a workflow that would work with MS but also with the reality of how the soft tissues were preserved.”
These efforts reflect a broader shift within paleoproteomics: from simply identifying ancient species to reconstructing aspects of physiology and health that were once thought permanently inaccessible.
The limitations of paleoproteomics
Despite its promise, paleoproteomics remains a technically demanding and young field.
One big question concerns preservation limits. Scientists know proteins can survive vastly longer than DNA under favorable conditions, but they do not yet know where the upper boundary lies.
“We’ve demonstrated the recovery of proteins 20–25 million years old from the very cold archipelago north of Canada. But at the same time, we don't know if that was just a lucky strike,” said Cappellini.
Contamination also poses persistent risks. Ancient samples can easily acquire modern proteins through excavation, handling, or laboratory procedures. Researchers must distinguish endogenous proteins from microbial contaminants that accumulated after burial.
Interpretation presents another hurdle. Modern protein databases are built largely from living organisms, making ancient, degraded proteins difficult to identify accurately.
“MS improves year on year in terms of the sensitivity and the resolution, and with AI, there's this boom in bioinformatics and our ability to improve our database searching,” Morton-Hayward said. “But the reality that we're working with in paleoproteomics is that 95% of our spectra go unidentified. It's called the dark paleoproteome—an enormous amount of information that, although we've managed to extract it in the lab, we can't analyze.”
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“To get a hold on this dark paleoproteome, we have to focus more on the chemistry,” she added. “At the moment, it's kind of like we're playing snap with the wrong deck of cards. We're playing with ancient proteins and living proteins, and they don't necessarily match.”
Researchers are starting to turn to AI, degradation modeling, and experimental decay studies to better understand how proteins change over time. The long-term goal is to build reference frameworks specifically tailored to ancient molecules rather than modern ones.
Meanwhile, paleoproteomics is beginning to merge with other approaches. Combining proteins with ancient DNA, isotopic analysis, and archaeological evidence could eventually provide multidimensional reconstructions of extinct organisms and past populations.
“Ancient DNA was able to give us genetic information from material that is mostly from Europe or Central Asia, and it's no more than half a million years old,” Cappellini said. “But if you consider that the process of human evolution took place over seven to eight million years, it's only the terminal part we’re seeing.”
The future of paleoproteomics
Paleoproteomics is still catching up technologically with genomics and clinical proteomics, but its trajectory is unmistakable. What began as a niche analytical technique is rapidly becoming one of the most important tools for studying deep evolutionary history.
“In paleoproteomics, we're always playing catch-up to clinical proteomics,” Morton-Hayward said. “Proteins are fairly complicated enough, and then you add in death and decomposition, and this curve just accelerates in terms of complexity. But you have to start somewhere.”
That “somewhere” now stretches millions of years into the past.
“At the same time, we are not there yet, because the limits that are associated with the recovery of relatively small proteins. The total coverage in terms of amino acids that we can have at the moment is in the order of hundreds. We don't even reach 1000 amino acids in the million-year range. If we could multiply this by a factor of 100, then we could start to answer different kinds of questions,” said Cappellini.
Even with these limitations, by extending molecular analysis far beyond the reach of DNA, paleoproteomics is turning fossils into biochemical archives. Teeth, bones, and preserved organs are beginning to reveal not only who ancient organisms were, but potentially how they functioned, adapted, and lived.
For scientists searching the deep past, proteins may prove to be biology’s most enduring storytellers.
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