Leprosy: holding steady for 400 years

0613_leprosy_skullIn a new Science article, Genome-wide comparison of medieval and modern Mycobacterium leprae, Verena J. Schuenemann and colleagues managed to amplify ancient pathogen DNA from individuals suffering from leprosy hundreds of years ago. Leprosy is one of my many dorky fascinations. This winter, I dragged my sister to visit a former leper colony on the gorgeous Hawaiian island of Molokai. Getting there involved riding a mule down a sheer cliff face–it was a pretty exhilarating experience for someone with a life as tame as mine. And the palpable sense of history there, where a few patients with Hansen’s disease still reside, was really moving. Anyway, you can imagine that I was pretty stoked to see this study on leprosy in the headlines.

These scientists gathered the bones and teeth of 22 medieval skeletons from Denmark, Sweden, and the UK, hopeful that at least a few would yield quality DNA. And they were in luck! Dealing with ancient DNA is always a tricky business, and the researchers were ready with a special capture technique to enrich for M. leprae DNA, making it easier to sequence by getting rid of contaminating DNA from other species. One tooth from Sweden, however, provided M. leprae DNA that was in such great condition that they didn’t even need to use the capture method (you can see the skull from which the tooth came here). It yielded a whole genome sequence on its own–and the tooth even contained more M. leprae DNA than human DNA. Pretty amazing!

In fact, the superb preservation of the M. leprae DNA was a recurring theme throughout the article. It actually sort of threw a wrench in the works, since one quality control measure that researchers use when dealing with ancient DNA is looking at the pattern of nucleotide misincorporation patterns, to make sure they are consistent with an ancient source. What does that mean? As DNA ages, more and more DNA bases are replaced by faulty copies, or nucleotide misincorporations. Therefore, ancient DNA should have a lot of nucleotide misincorporations. Usually, if an “ancient” sequence looks brand new, in terms of nucleotide misincorporations, you know you’re in trouble. You may be inadvertently studying modern DNA that has somehow contaminated your samples or laboratory. This case seems to be the exception, however. The other quality control measures in this study–like blank controls, independent replication by other groups, and identification of mycolic acids consistent with M. leprae–all looked good. It’s probable that the great preservation of the M. leprae DNA was due to the waxy, cell wall that surrounds the bacteria. Apparently, it protects the DNA inside from degradation. The same thing goes for M. tuberculosis, the cause of tuberculosis and a close relative of the leprosy bacterium; researchers have had pretty good luck finding ancient M. tuberculosis DNA that is in good shape. If you’re interested, you can find a couple of neat examples of recent ancient tuberculosis studies here and here.

Schuenemann et al. were able to obtain whole genome sequences from five of their ancient samples, representing each of the three countries (Sweden, the U.K., and Denmark) and dating from the 10th-14th centuries. They compared these whole genome sequences to 11 obtained from modern strains, which were collected in places like India, Thailand, the US, Brazil, Mali, the Antilles, and New Caledonia. And they found that there were very few genetic differences between all of the strains. In fact, one of the major conclusions that emerged from this article is that leprosy strains have changed very little since Medieval times. After building a phylogeny (i.e. a family tree for the bacteria), Schuenemann and colleagues found that the ancient European strains were most closely related to modern strains from Turkey and Iran. This may indicate that Medieval European strains originated in the Middle East. One popular hypothesis about why the number of leprosy cases in northern Europe shot up around the 11th century is that knights returning home from the Crusades ignited epidemics–this paper adds a little more evidence to support that theory.

The rather sudden disappearance of leprosy from Europe has been an enduring mystery in the annals of historical epidemiology. It has been estimated that there were almost 20,000 leprosaria (or leprosy hospitals/colonies) in Medieval Europe. Today, there is only one remaining colony for patients with Hansen’s disease in Europe. Obviously, antibiotics helped drive down the prevalence of the disease. But hundreds of years before we discovered a cure, leprosy was vanishing from Europe. Why? A change in the bacteria that made it less transmissible? Or a change in Europeans that made them less susceptible? Nobody knows! One of the authors’ conclusions that I found particularly interesting was that because there were so few genetic differences between ancient strains and modern strains, it’s unlikely that changes in the pathogen can explain why leprosy is no longer such a scourge. They hypothesized that other factors (like co-infections, social factors, or host immunity) were probably responsible for the susceptibility of Medieval Europeans to leprosy. These findings and this conclusion are similar to those that emerged from a comparison of ancient Y. pestis strains obtained from victims of the Black Plague and modern Y. pestis strains–there were no unique genetic differences in the ancient strain, so the authors (many of whom also worked on this leprosy article) concluded that genetic characteristics of the pathogen was unlikely to explain why the Black Plague was so deadly.

I think the authors may well be correct about host factors accounting for the decline of leprosy in Europe. There is no question in my mind that things like nutrition and hygiene play a very important role in susceptibility to infection. But I also think ruling out important pathogenic changes because there are few genetic differences between strains is risky. When you see that a particularly virulent strain of bacteria has recently acquired a big chunk of DNA, especially one that contains genes linked to virulence, it’s easy to pinpoint the basis for that microbe’s nastiness. But failing to find big genetic differences doesn’t necessarily mean that important changes aren’t present. As we know from studies of viruses (like influenza and the λ bacteriophage) and bacteria (like Y. pseudotuberculosis), one or two tiny mutations can have a large effect on things like transmission and virulence. It’s really hard to look at a smattering of DNA substitutions and know what they mean! I’ll be curious to see what we learn about some of the genetic changes identified in the study in the future.

Congratulations to Schuenemann and the other scientists involved in this work for such an exciting study. I really envy the people who study Mycobacteria. I worked on the bacterium that causes syphilis, T. pallidum, for a long time. Being able to sequence a few ancient strains of this microbe could go a long way toward solving the mystery of this infection’s origins (you can find some of my relevant articles here and here and here). In particular, did Columbus introduce this disease into Renaissance Europe after returning from the New World? Unfortunately, T. pallidum DNA seems to be very sensitive to degradation. So there doesn’t seem to be much hope that ancient DNA is going to come to the rescue in this case! With the constantly improving sensitivity of sequencing techniques, though, who knows what the future holds?! The technological advances that have emerged since I began graduate school, ten years ago, have transformed the face of science. It’s an exciting time.

One thought on “Leprosy: holding steady for 400 years

  1. It makes sense that the Medieval strains would have originated in the Middle East. The Bible has several references to leprosy (if the cases were indeed leprosy) so we know it was in the area.
    I think it’s interesting that in BraveHeart, Robert Bruce’s father is shown as a leper, since he did travel to the Middle East.

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