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Diagnostics Clinical care, Forensics, Genetics and epigenetics, Histology, Profession, Biochemistry and molecular biology, Omics

Connecting Past to Present

When diagnosing or studying a particular disease, where do you begin? Perhaps with a patient’s self-reported symptoms or their medical and family history. Perhaps with blood and tissue samples. Perhaps with a clinician’s report and differential diagnosis. But what if you had none of these things – and what if your patient had lived hundreds or even thousands of years in the past? How would you pursue a disease investigation in an ancient person or population, and what impact could that information have on the modern study of disease?

A brief history of paleopathology

Paleopathology is the study of disease in the past. Most often, of course, disease is studied in human remains – so, when archeologists dig out old skeletons from the Stone Age or look at mummies from ancient Egypt, they might see signs of disease. And that leads to questions. Which diseases hit when? When did they start? How can we trace them? How long has a particular disease been around? It was questions like these that inspired the field; we wanted to provide temporal depth to human diseases as we know them today.

In the beginning, paleopathologists could only study diseases that left morphological traces on human remains, usually bone. As a result, our early colleagues spent most of their time focusing on chronic diseases, such as leprosy, tuberculosis, or syphilis – those that would leave their mark. In recent years, though, we’ve seen a real revolution. Advances in DNA technology have enabled us to extract ancient DNA from even very old human remains – and that opens up the field to study not just chronic diseases, but also acute infections. We can now extract and analyze human DNA from bones to learn more about ancient diseases and their effects on populations, but it doesn’t stop there – we can also look for traces of bacterial DNA to study which pathogens existed when.

Perhaps even more importantly, we are able to gain much more information about the natural history of the diseases themselves. By looking at how diseases develop alongside humans and other animals, we can gain a much more fine-tuned picture of how diseases evolve, how they co-evolve with humans, and how that process is affected by the huge cultural changes that human populations have undergone throughout even their recent history. An example might be animal husbandry; as soon as a group domesticates animals, they increase their close contact with those animals, which changes the pathogen load to which those humans are exposed – bacteria, viruses, parasites… So now, more than ever, we can look not only at which diseases existed in different past populations, but also how our actions can affect their evolution.

That latter aspect, I think, is very exciting, because it can also give us predictive knowledge. Knowing more about how diseases and pathogens developed in the past may give us ideas about how they might continue to develop. So even as we look at new diseases around the world, we must remember that there is knowledge to be gained by observing the evolution of pathogens from their earliest days to the present.

On a smaller scale, it’s also tremendously interesting to know exactly which diseases existed at any given time in a specific past population. What was the level of syphilis in early 16th-century Europe? How prevalent was leprosy in medieval European populations? What degree of malnutrition did various populations suffer? Everything from the close examination of a single skeleton to the study of entire past populations can add to archeologists’ interpretation of past society and help them reconstruct the lives of our predecessors.

The study of tuberculosis, in particular, has become much richer with the advent of ancient DNA. Suddenly, we’re learning about how it may have cross-infected between different species and how Mycobacterium species traveled between continents – not just via humans, but also other mammals. My colleague Jane Buikstra (see here) has actually published a Nature paper (1) about the advent of tuberculosis in South America (and the Americas as a whole) – a story with a surprising ending! Our ability to use modern DNA techniques to investigate the genomes of ancient Mycobacterium strains has given us a better understanding of how tuberculosis was able to travel from the Old World to the New.

And that’s just one example in an area where we are rapidly accumulating knowledge. I think it’s vitally important to improve our understanding of how tuberculosis spreads, because it is still a global disease and infection rates are actually increasing (in part because we don’t practice antibiotic stewardship as well as we should, so strains with antimicrobial resistance are on the rise). The more we know about how these bacteria react in a “micro-evolutionary” sense, the better we can approach developing new antibiotics to manage tuberculosis.

I think it’s vitally important to improve our understanding of how tuberculosis spreads, because it is still a global disease and infection rates are actually increasing.
Mandible with pronounced destruction due to syphilis.

On the more enigmatic side, we have diseases like leprosy. It doesn’t seem like leprosy would be a mystery to us; it’s familiar in the sense that it’s written about in the Bible. We have lots of skeletons from medieval Europe with leprosy – and, unfortunately, it still exists in some developing countries. But it’s not as clear-cut as it seems. For instance, I’m from Denmark, where we have almost no evidence of leprosy before the year 1000, give or take. But then, around the 12th or 13th century, it explodes. Suddenly, there’s an abundance of skeletons showing evidence of leprosy, and paleo-epidemiological studies (2) point to almost a quarter of the population carrying the pathogen (Mycobacterium leprae). And then, in the 16th century, it disappears again just as suddenly. Why did such a disease, known since Biblical times, abruptly turn up in Europe, have an explosive run through the continent, and then more or less completely vanish, except for certain small areas? We don’t know! 

Some paleopathologists hypothesize that it’s because we began living much closer to cattle, cross-infecting us with tuberculosis – another mycobacterial disease that may have conferred some protection against leprosy. Others have suggested that climate change might indirectly have played a role. For example, there was a warming period in the 12th century, which was followed by the so-called “Little Ice Age” in the 14th century. The Little Ice Age had severe societal repercussions in terms of crop failure and famine, and the widespread poverty may have been a factor in the spread of leprosy in northern Europe. Still others are interested in pockets where the disease remained after its disappearance in most places. In the more remote areas of Norway, for example, they had leprosy right up until the 18th century – much later than anywhere else. The answer is probably a combination of many reasons but, ultimately, no one really knows for sure – at least, not yet. Such questions make this field incredibly exciting.

Digging into disease

We obviously associate very closely with archeologists, so sometimes we actually join excavations to help unearth human remains. On other occasions, when such remains are found on a dig, they’re sent to us for further examination. I think our process is somewhat similar to that of pathologists studying living or recently deceased patients and populations. We look at how many individuals were found, whether they were male or female, the age ranges, and so on – and we take note of distinguishing features like healed fractures or signs of malnutrition. Sometimes the signs of disease are subtle, like the skeletal changes associated with syphilis; sometimes less so, like a collapsed vertebral column caused by tuberculosis. So, once all of that information has been tabulated, we can collate it and use it.

One clear difficulty for us that is not faced by clinical pathologists is the human remains themselves. Whichever way you look at it, the remains are always merely a subset of a once-living population. Not everybody dies where they lived; not everybody gets buried where they lived or died; not everybody is located and excavated 5,000 years later by archeologists; and, even if you do happen to be one of the lucky few, so to speak, not everybody is preserved well enough that we can look for signs of disease.

The Paleopathology Association

The Paleopathology Association, founded in 1973, is a global organization with members from all over the world. We have meetings every year in northern Europe, every second year elsewhere in Europe, and every second year in South America – and we will soon have a meeting in South Korea. The field is attracting a lot of younger researchers, especially with new developments in molecular biology, genetics, proteomics, and similar areas. Everyone is welcome to join, including students, for whom we have a specific group within the association.

For more information or to join the Paleopathology Association, please click here.

The limited nature of our evidence skews our findings and makes it difficult to answer key questions. For example, what were the demographics of those infected by a particular disease? What was its epidemiology? How many were infected? What was the disease actually like? We can’t just take a cross-section of the population as a modern epidemiologist could; we’re always constrained by the skeletal or mummified material.

A changing field

We may suffer a dearth of evidence, but technological advances are helping us get a better handle on it. Previously, many diseases could only be found macroscopically and morphologically, limiting us to long-suffering patients whose bones had developed characteristic changes. (Bone is, after all, a tissue with slow turnover and subject to non-specific changes that could be indicative of a number of diseases and disabilities.) 

Now, thanks to the development of specific primers to pathogenic DNA (which medical researchers and clinicians use to develop vaccines, select antibiotics, and so on), we can interrogate ancient DNA for bits and pieces of the genomes of pathogens so that we can find out what infectious agents existed in a given population. It’s also possible, of course, for an individual’s own DNA to pinpoint heritable diseases that we could not find using skeletal evidence alone. One example is hemochromatosis – a genetic disease that leads to excessive uptake of dietary iron, which accumulates in the liver and ultimately leads to cirrhosis and liver failure. It turns out that, based on ancient DNA analysis, hemochromatosis is more pronounced in northern Europe – it’s even been called the Celtic or Viking disease because of its high frequency in Scandinavia, parts of England, and northern France.

The theory is that the genetic defect causing hemochromatosis arose in the Bronze Age or early Iron Age in northern Europe. It’s possible that it survived and was passed down through generations because it might have been a beneficial mutation; if you are infested with parasites and intestinal worms (common in those times) and losing a lot of iron, it is hazardous to your health – especially if you are vulnerable for other reasons, such as in the case of pregnant women. Today, it’s no longer beneficial – we get plenty of iron and we are unlikely to be infested with all kinds of parasites. We just haven’t lost the mutation.

We’ve seen a similar evolution in the Mediterranean area with thalassemia. If you have mild thalassemia, like many people of Mediterranean descent, it doesn’t result in a problematic degree of anemia – but it does confer some protection against malaria. In an era before prophylactic treatment, it would have been a valuable trait to possess.

These two examples show what fascinating data we can obtain by studying ancient DNA – what gene variants are common, which variants are correlated with disease, how many carriers there may have been (and who they were), and so on. DNA analysis really has opened up new and exciting areas of exploration for paleopathology!

I think it’s clear that paleopathology has real relevance to the understanding (and diagnosis) of modern-day disease.
Cartilaginous exostoses.
Vertebrae with tuberculosis (Pott´s spine): a) photograph; b) radiograph; c) coronal CT scan.
Clinical contributions

Clinical advances often drive the forward progress of paleopathology because the disciplines are so closely linked. And I think this shared evolution is very important, because it lets us correlate past presentations of disease with current ones. Here, again, leprosy is a good example. Much of the key research in the paleopathology of leprosy was performed in the 1950s and 1960s by Vilhelm Møller-Christensen, who was not a specialist, but an ordinary general practitioner in Denmark. He began assisting archeologists with the excavation of medieval cemeteries where he lived by examining the bones. In fact, that’s how the study of leprosy in medieval human remains began – with Møller-Christensen discovering so many skeletal changes related to the disease. Eventually, he started visiting the Philippines, Thailand, Nepal, and areas of Africa where leprosy was prevalent, because he wanted to parallelize his osteological findings with the present-day development of the disease.

I think it’s clear that paleopathology has real relevance to the understanding (and diagnosis) of modern-day disease. It’s not just about the horrible diseases people suffered from in days of yore. It’s a discipline that is constantly changing and evolving, and one that exists alongside clinical medicine with mutual benefits. The vast array of tests available in clinical laboratories can be useful to us, and our long time perspective can be useful to research and clinical pathologists.

Becoming a paleopathologist

I originally started training as a forensic pathologist. I wanted to improve my ability to identify human remains in a forensic context but, in Denmark, we (fortunately) don’t have many cases that would give me such opportunities. Looking at thousands of skeletons from the past offers the closest possible experience, so I started investigating the remains of Viking Norse from Greenland. As you can imagine, I found it fascinating, so I started studying Greenland mummies, performing CT scans, and delving ever deeper into the world of ancient remains. Combine that with my medical training, and it’s obvious why I found paleopathology so intriguing.

Currently, I’m head of the University of Copenhagen’s forensic medicine department, but a lot of my research is in the area of paleopathology. My colleagues in the Paleopathology Association have diverse backgrounds; some are medically trained, some come from anthropology, and some are experts in archeology or other related disciplines. I think that’s what makes our association so interesting – we have a great mix of people; not just doctors and anthropologists, but also biologists, geneticists, and other experts from all sorts of fields. The cross-disciplinary nature of our group – and our work – means we have truly creative discussions at our meetings.

If you’re interested in paleopathology, I would recommend contacting people who work in the field. Ideally, find someone local who does the type of work that interests you, perhaps at a university or a museum – and then get involved! Most of the people I know in this field got here by simply pursuing a personal interest. A good example is the late, well-known paleopathologist Art Aufderheide, a clinical pathologist working in the United States who was asked to look at some tissue specimens from Egyptian mummies. The work captured his imagination to the point where he drove a great deal of research in paleopathology, developing methods to rehydrate and stain burial tissue and carrying out a lot of diagnoses on ancient tissues. His story also shows that you don’t necessarily have to leave the clinic to participate. We often go to clinical pathologists for help with our work – for instance, developing better stains to look at histological specimens, or using tissue microscopy to better examine preserved soft tissue in mummies. No matter what your field of pathology or your particular research interests, there is a place for you in paleopathology.

Niels Lynnerup is Head of the Department of Forensic Medicine at the University of Copenhagen, Denmark.

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  1. KI Bos et al., “Pre-Columbian mycobacterial genomes reveal seals as a source of New World human tuberculosis”, Nature, 514, 494–497 (2014). PMID: 25141181.
  2. JL Boldsen, “Leprosy in Medieval Denmark--osteological and epidemiological analyses”, Anthropol Anz, 67, 407–425 (2009). PMID: 20440960.

About the Author

Niels Lynnerup

Niels Lynnerup is Head of the Department of Forensic Medicine at the University of Copenhagen, Denmark

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