A new Oxford method retrieves proteins from ancient soft tissue, uncovering brain health markers and expanding knowledge of ancient disease and biology.
Researchers at the Nuffield Department of Medicine, University of Oxford, have developed a new method that could soon unlock a vast amount of biological information stored in the proteins of ancient soft tissues. Their findings, which may mark the beginning of a new era in palaeobiological research, were recently published in PLOS ONE.
Soft tissues such as the brain, muscle, stomach, and skin can reveal unique insights into the past and into the lives of individuals. However, this valuable source of information has remained mostly out of reach for scientists. In the new study, a team led by postgraduate researcher Alexandra Morton-Hayward (University of Oxford) introduced the first reliable method for extracting and identifying proteins from ancient soft tissues and tested it on archaeological samples of human brain tissue.
“Until now, studies on ancient proteins have been confined largely to mineralized tissues such as bones and teeth,” says Morton-Hayward. “But the internal organs – which are a far richer source of biological information – have remained a ‘black box’ because no established protocol existed for their analysis. Our method changes that.”
Breaking open ancient cells
One of the main challenges was finding a reliable way to break open the cell membranes and release the proteins inside. The team tested ten different approaches on samples taken from 200-year-old human brains excavated from a Victorian workhouse cemetery. They found that urea, a key component of urine, was effective at breaking down the cells and releasing the proteins.
Once extracted, the proteins were separated using liquid chromatography and then identified through mass spectrometry, a technique that distinguishes proteins based on their mass and electrical charge.
To improve the process, the researchers added another step called high-field asymmetric-waveform ion mobility spectrometry, which separates ions based on how they move in an electric field. This combination increased the number of proteins identified by up to 40 percent, making the method especially effective for analyzing degraded or complex samples.
Morton-Hayward added: “It all comes down to separation: by adding additional steps, you are more likely to confidently identify molecules of interest. It is a bit like dumping out a bucket of Lego: if you can start to discriminate between pieces by color, then shape, then size, etc. the better chance you have of making something meaningful with it all.”
Largest palaeoproteome ever recorded
Using the combined method, the team identified over 1,200 ancient proteins from just 2.5 mg of sample – by far the largest and most diverse paleoproteome ever reported from any archaeological material.
The researchers point out that proteins are an ideal vehicle to navigate the recent and deep past, as they survive far longer in the archaeological record than DNA, and can tell us about the lived experience of an individual, beyond their genetic blueprint.
Working at the Centre for Medicines Discovery at the University of Oxford, the team identified a diverse array of proteins that govern healthy brain function, reflecting the molecular complexity of the human nervous system – but also identified potential biomarkers of neurological diseases, like Alzheimer’s and multiple sclerosis.
“The vast majority of human diseases – including psychiatric illness and mental health disorders – leave no marks on the bone, so they’re essentially invisible in the archaeological record,” says Morton-Hayward. “This new technique opens a window on human history we haven’t looked through before.”
A leap beyond bones and DNA
Since less than 10% of human proteins are expressed in bone compared to around 75% in internal organs, this technique promises to vastly expand our understanding of ancient diet, disease, environment, and evolutionary relationships. Senior author, Professor Roman Fischer, Centre for Medicines Discovery at the University of Oxford, added: “By enabling the retrieval of protein biomarkers from ancient soft tissues, this workflow allows us to investigate pathology beyond the skeleton, transforming our ability to understand the health of past populations.”
The method has already attracted interest for its applicability to a wide range of archaeological materials and environments – from mummified remains to bog bodies, and from antibodies to peptide hormones.
Dr Christiana Scheib, Department of Zoology at the University of Cambridge, who was not involved with the study, said: “Ancient soft tissues are so rarely preserved, yet could hold such powerful information regarding evolutionary history. It is key to first develop the best way to obtain relevant information from these materials, which is what this study does. This type of fundamental experimental work is crucial for the field to move forward. The study is well-designed and I look forward to seeing what will be gleaned from the future protein data that this work has enabled.”
Reference: “Deep palaeoproteomic profiling of archaeological human brains” by Alexandra Morton-Hayward, Sarah Flannery, Iolanda Vendrell and Roman Fischer, 28 May 2025, PLOS ONE.
DOI: 10.1371/journal.pone.0324246
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