Scientists Solve an 800 year old Mystery Related to Paget’s Disease

Funding from the Paget’s Association has helped scientists solve an 800 year old mystery related to Paget’s disease. Scientific research at the molecular level, on a collection of medieval skeletons from Norton Priory in Cheshire, could help rewrite history after revealing they were affected by an unusual ancient form of the disorder.

The study was made possible with funding from the Wellcome Trust, the Paget’s Association and the Michael Davie Research Foundation. Coordinated by researchers at the University of Nottingham, the research involved analysing proteins and genetic material preserved in the bones and teeth that are more than 800 years old.

The work suggests that ancient remains can hold a chemical memory of disease and that similar molecular analysis could be used to explore the evolution of other human disorders.

The study, published in a highly respected journal*, is significant because it indicates that ancient Paget’s disease may have been far more common than the modern disease and developed much earlier in life.
Paget’s disease is nowadays the second most common metabolic bone disorder and affects around 1% of the UK population over the age of 55, with an especially high prevalence in the North West of England. Both genetic and environmental factors are important in the disease, a likely explanation for the regional variations in its incidence. Paget’s disease can result in the weakening of the affected bone, causing deformity, pain, and sometimes fracture. In very rare cases, a bone affected by Paget’s disease can develop osteosarcoma, a malignant bone cancer.
Dr Carla Burrell, who received the Doreen Beck Research Bursary Award from the Paget’s Association, together with Professor Silvia Gonzalez from Liverpool John Moores University, found that more than 15% of the skeletons at Norton Priory had extensive disease throughout up to 75% of their skeletons, compared to the modern-day population with Paget’s disease, who typically have just one or a few bones affected. The research also revealed that the medieval disease started in young adulthood, whereas nowadays Paget’s tends to develop after the age of 55.

Surprisingly though, the medieval cases showed almost no evidence of the complications that are common in modern day Paget’s disease.

One of the skeletons analysed was thought to be that of William Dutton, a medieval Canon at the Priory who died in the late 14th century. He was aged between 45 and 49 when he died and had bone disease affecting more than 75% of his skeleton, including pelvic osteosarcoma. Further analyses indicated he had a marine-based diet typical of a high-status individual, and was local to the North West of England, pointing to some local environmental factor that may have triggered his disease.

Coordinating the project, Professor Robert Layfield from the Nottingham Paget’s Association Centre of Excellence (PACE), said: “X-ray analyses of medieval skeletons from the collection at Norton Priory first directed us to unusually extensive pathological changes resembling, but also very different, to modern day Paget’s disease.
We carried out a much closer inspection of the remains using a technique called paleoproteomics – protein sequencing using mass spectrometry. This technique allows analysis of bone samples at the molecular level by extracting proteins from the ancient bone cells. Remarkably these proteins are well-preserved, whereas DNA degrades over extensive periods of time. Effectively the proteins offer an insight into the biology of the cell when it was alive many hundreds of years ago.

We were able to identify one ancient protein that is diagnostic of Paget’s disease. This indicates the people who died at Norton were affected by a very different form of Paget’s disease to what we see today. Our research shows how proteomics can be used to examine and diagnose disease in ancient bones, and importantly also in ancient teeth. It backs up the theory that Norton Priory and perhaps the North West, in general, was a hotspot for this early form of Paget’s and opens up new questions about its natural history and risk factors.”
A major finding in parallel to protein sequencing was the successful analysis of ancient microRNAs in the 600 year old skeleton that was affected by pelvic osteosarcoma.

MicroRNAs are genetic molecules that control how active our genes are and contribute to almost all genetic diseases ever studied. Specific microRNA patterns are used to determine different disease types and the findings in this study correlate with modern day microRNA patterns of bone cancer.
Analysis of ancient microRNAs has also opened up an entirely new field of research using archaeological samples, as microRNAs were thought to be unstable and usually have to be studied in fresh samples.
Dr Darrell Green, from the University of East Anglia’s Norwich Medical School, received the Allan Reid Student Research Bursary Award from the Paget’s Association to investigate osteosarcoma, which is today, a very rare but devastating complication of Paget’s disease. Dr Green analysed the skeleton affected by osteosarcoma and said: “MicroRNAs have never been investigated in ancient samples before because it seemed patently obvious that given their genetic structure they would degrade very quickly.

We developed a new, more sensitive technique to capture microRNAs in all types of samples and were surprised to find we detected microRNAs in the 600 year old bone cancer. This shows that given the correct preservation conditions, microRNAs are more stable than anybody thought so our new technique could be applied to museum samples that hold a wealth of data on biological and medical history.”

Lynn Smith, Senior Keeper at Norton Priory Museum and Gardens said “The results of the scientific research into an ancient form of Paget’s here at Norton Priory have been a real surprise and are adding a huge amount to our knowledge and understanding of this unique medieval population. It is very rare for an archaeological collection to be used in such cutting-edge research and as such it has been both a privilege and a career highlight for me. The results will not only help re-work our interpretation of the site and the individuals that had connections with the Priory but will also help inform modern medical practice and future research”.

By further applying the methods developed in the project the researchers also hope to gain a better understanding of what daily life was like for our ancestors affected by this, and other, ancient bone disorders.

The next stage of the research will be to determine what the ancient environmental triggers for Paget’s disease might have been, which may help doctors understand the fall in incidence of modern-day disease observed over the past few decades. The Paget’s Association will watch with interest this developing project, which may lead to information crucial to preventing Paget’s disease from developing in those susceptible to it.

For the full article follow this link to the National Academy of Sciences of the United States of America. Visit information on the University of Nottingham website for more information about their work.

VISIT - If you would like to visit Norton Priory Museum and Gardens, the Paget's Association is holding a Members' Day in September 2019. Follow this link for details.

* Proceedings of the National Academy of Sciences of the United States of America (PNAS)