By the close of the 15th century, chaos reigned in Naples, Italy. At the invitation of Pope Innocent VIII, the French King Charles VIII invaded the city with 25,000 troops. Soon after, a terrible new disease appeared among the soldiers and the prostitutes who accompanied them. Boils as big as acorns that burst and left scabs, terrible joint pain, rotting flesh, and a revolting odor...

The pale, corkscrew-shaped bacterium responsible for the outbreak, Treponema pallidum, was identified in 1905, and the prevalence of the infection plummeted in the developed world after the discovery of antibiotics. Still, roughly 12 million people are diagnosed with syphilis each year, and it remains an important public health problem in low-income countries.

There continues to be disagreement about where syphilis originated. Much evidence seems to point the finger at Christopher Columbus and his crew, who may have picked up the pathogen on their legendary first visit to the New World. Some have claimed that the disease existed in Europe before Columbus’s time, however, with environmental or social changes during the Renaissance causing it to erupt with a vengeance. Historians have long questioned whether or not vague passages in famous texts describe syphilis, and arguments over the dates of pertinent historical documents are common.

Recently, many researchers, our group included, have taken a new approach to the study of the origin and evolution of syphilis and its cousins, and the breadth of these diseases’ reach today. Leveraging techniques from genetics, biological anthropology, and wildlife disease ecology, syphilis researchers are now beginning to answer questions that have been pondered for hundreds of years. The skeletal, genetic, and ecological information scientists are now uncovering could inform our understanding of how T. pallidum has evolved and how we can best control it today.

Looking bone-deep

© BIOPHOTO ASSOCIATES/SCIENCE SOURCE; © BIOPHOTO ASSOCIATES/SCIENCE SOURCE OTIS HISTORICAL ARCHIVES NAT'L MUSEUM OF HEALTH & MEDICINE/WIKIMEDIA COMMONSAfter rulers from across Italy banded together to expel King Charles VIII from Naples, the French soldiers returned home, taking syphilis with them. Medical historians have used historical documents to trace the rapid spread of the infection across Eurasia. Going backward in time, however, to uncover where syphilis originated, has proven more difficult.

The timing of the first epidemic led contemporary scholars to postulate that syphilis originated in the New World and was transmitted to the Old World by Columbus and his crew, who returned to Europe just before King Charles VIII’s invasion of Naples. Known as the Columbian hypothesis, this explanation dominated for hundreds of years. Then, in the 20th century, researchers proposed the pre-Columbian hypothesis, suggesting that syphilis may have existed in the Old World long before the Neapolitan outbreak without being recognized as a distinct disease until the Renaissance. Perhaps prior to 1495 it was conflated with other infections, such as leprosy, scholars posited.

Another theory, known as the unitarian hypothesis, also emerged. It suggests that syphilis, as well as the related diseases yaws and bejel, are caused by identical types of T. pallidum. Like syphilis, yaws and bejel are chronic, debilitating diseases. Unlike syphilis, they are not sexually transmitted and are usually contracted in childhood. Yaws is found in tropical regions of the world and spreads via skin-to-skin contact, while bejel is found in arid regions, such as the Middle East, and appears to spread via contaminated utensils and drinking vessels. According to the unitarian hypothesis, T. pallidum manifests in different ways depending on environmental conditions and other factors, such as the age at which a person becomes infected. If this hypothesis is correct, then the Renaissance epidemic of syphilis could simply reflect the response of the pathogen to changes in the social and sexual environment of the time, such as improved hygiene and lax urban sexual mores.

To address these possibilities, researchers have turned to skeletal remains. Syphilis, yaws, and bejel—collectively known as the treponemal diseases—sometimes leave a telltale signature upon the skeleton: bone lesions that develop as a result of infection. Although most skeletal lesions do not provide conclusive evidence of treponemal disease, a few lesions are diagnostic. A suite of crater-like areas on the exterior of the skull called caries sicca, for example, can be confidently attributed to treponemal disease, as can shinbones that are both swollen with new growth and pitted with shallow cavities. By searching for these diagnostic lesions among skeletons from ancient populations, biological anthropologists can learn more about where treponemal disease was—and wasn’t—over the course of human history.

Much evidence seems to point the finger at Christopher Columbus and his crew, who may have picked up the pathogen

on their first visit to the New World.

In 2005, paleopathologists Mary Lucas Powell, professor emeritus at the University of Kentucky, and Della Collins Cook of Indiana University found indisputable cases of treponemal infection throughout the Americas, some dating back to the pre-Columbian New World. Based on the ages of the affected skeletons, many of which were juvenile, most researchers believe that the disease was not transmitted sexually, as syphilis is known to be. It’s possible that this New World treponemal pathogen was transported by Columbus’s crew across the Atlantic, evolving into a sexually transmitted form because the clothing worn by 15th-century Europeans would have limited the potential for skin-to-skin transmission.

But the skeletal evidence for infection in the Old World is more ambiguous, making it difficult to pinpoint the appearance and spread of the pathogen on the eastern side of the Atlantic Ocean. In 1988, one of us (G.J.A.) reviewed available research on this subject and found no compelling evidence that treponemal disease was present in pre-Columbian Europe.1 Since then, however, a steady trickle of reports describing Old World skeletons with lesions that predate Columbus’s New World voyages, sometimes by thousands of years, has appeared in the literature.

In light of the new evidence, we performed another comprehensive review in 2011.2 After establishing rigorous, evidence-based criteria for dating and diagnosis, we found a number of Old World cases with a strong treponemal diagnosis and a number with solid pre-Columbian dates. Strikingly, however, we did not find a single case that had both a compelling diagnosis and a reliable date, leading us to question whether the pathogen did indeed appear in Europe before Columbus sailed the ocean blue. Of course, some areas of the Old World, like sub-Saharan Africa and Asia, have received much less attention from archaeologists and paleopathologists, and ancient skeletons with diagnostic treponemal lesions may be waiting there to be discovered.

DNA tells all

With the enormous advances in genomics made in the past two decades, it was only a matter of time before genetics answered the basic question that had plagued researchers for years: are the pathogens that cause syphilis, yaws, and bejel genetically distinct? In 1998, researchers sequenced the genome of a common lab strain of syphilis, originally isolated from a patient in the Washington, DC, area some 86 years earlier. This sequence, along with data from other treponemal strains, validated the current convention of dividing the bacterium into three different subspecies: T. pallidum subsp. pallidum (syphilis), T. pallidum subsp. pertenue (yaws), and T. pallidum subsp. endemicum (bejel).3 Within each of these subspecies exist various strains.

Genetics also affords researchers the ability to track the evolution of syphilis. To this end, we collected T. pallidum strains from around the world and used them to construct a phylogenetic tree.4 Our analysis suggested that the closest genetic relatives of syphilis strains are non-sexually transmitted, yaws-causing strains of T. pallidum found in the South American country of Guyana. These strains were collected by Mike Silverman of the University of Toronto and colleagues from children in remote, indigenous communities who had developed unusual lesions. The sores were found in areas of the body, such as the shins, that were consistent with yaws; however, they were more similar in appearance to the smooth chancres of syphilis. Thus, in terms of both genetics and clinical manifestations, these South American strains appear to occupy a space midway between yaws and syphilis. This supports the idea that modern syphilis-causing strains descended from a non-sexually transmitted pathogen in the Americas. However, this study also yielded evidence that some kinds of treponemal disease may have been present in the pre-Columbian Old World.

Unfortunately, with only a small number of T. pallidum strains available to study, a rigorous phylogeographic analysis is difficult. We currently have only five laboratory strains of T. pallidum subsp. pertenue and two strains of T. pallidum subsp. endemicum; even the number of T. pallidum subsp. pallidum strains is relatively limited, with most coming from North America. And because this bacterium can’t be grown in a petri dish, gathering new strains is not easy, typically involving the infection of a suitable rodent with bacteria from a human lesion. In the unlikely event that the strain takes hold, researchers must passage the bacteria through a series of animals in hopes that they will someday grow at a reasonable rate. This is a lengthy, expensive, and laborious process, and due to the scant quantities and poor quality of T. pallidum DNA in infectious lesions, obtaining whole genome sequences from swabs and biopsies has proven difficult. Moreover, yaws is often found in remote, isolated communities, and bejel is exceedingly rare. Although one bejel case was reported from Iran last year, the last reported case before that occurred in Turkey nearly 20 years ago.

Another significant research challenge is the high degree of genetic similarity between T. pallidum strains. Phylogenetic trees based on so few genetic polymorphisms lack resolution, hindering the ability to draw conclusions about the relationships among and within the various subspecies. Moreover, most T. pallidum polymorphisms fall within a single family of rapidly recombining genes, which makes them unsuitable for phylogenetic analysis. Luckily, thanks to recent advances in whole-genome sequencing, a group led by David Šmajs of Masaryk University in the Czech Republic has been steadily turning out the genomes of syphilis- and yaws-causing laboratory strains.5,6 Perhaps one day it will be possible to obtain whole-genome sequences from bejel-causing strains and clinical samples as well.

An animal world

Another source of new genomes is the T. pallidum strains that infect various wild primate populations in Africa. For decades, positive serological tests have demonstrated that some populations of monkeys and apes suffer from treponemal disease. In West African monkeys, the manifestations are mild and appear to be limited to small sores around the muzzle and near the armpits, if they are present at all; in East African monkeys, the disease is more vicious.

In the late 1980s, researchers at Tanzania’s Gombe Stream National Park reported a gruesome disease that affected the genitals of resident baboons. By the mid-1990s, this disease had been detected at other national parks in the country. At Lake Manyara, New Scientist quoted a wildlife activist saying that “the genitals kind of rot away, then they just drop off,”7 and wardens confirmed that some males had died from the infection.

Working with our colleagues at the Tanzania Wildlife Research Institute (TAWIRI) and Sascha Knauf of the German Primate Center, we subsequently demonstrated that T. pallidum was responsible for these cases.8 Sequencing revealed that two strains collected at different sites in Tanzania exhibited genetic variability, but both were closely related to human yaws-causing strains. In fact, one of the strains was indistinguishable from a group of human yaws strains.9

Yaws is a chronic, debilitating disease that most commonly affects children. In the mid-20th century, the World Health Organization (WHO) launched a yaws eradication campaign that was tremendously effective, treating hundreds of millions of people worldwide with injections of penicillin and eliminating the disease entirely from many countries. Since then, however, yaws has returned. Cases have popped up in Ghana and the Republic of the Congo, as well as in remote areas in other parts of the world with little health infrastructure. These emerging cases—and a 2012 report in The Lancet, which showed that a single oral dose of azithromycin is as effective as a standard penicillin shot—led the WHO to launch a second counteroffensive in March 2012, more than 50 years after the conclusion of the first campaign. The number of active yaws cases today is unknown, but in 1995 the WHO estimated that 2.5 million individuals suffered from yaws or bejel and 460,000 of them were infectious.

Understanding animal-infecting strains of these pathogens is of particular importance to the eradication effort. One of the hallmarks of an eradicable disease is that it occurs only in humans. Otherwise, animals can serve as continuous reservoirs of infection, foiling attempts at eradication. Smallpox, the only human infectious disease eradicated to date, had no known animal reservoir. The two other diseases that are the subject of active eradication campaigns right now, polio and dracunculiasis (i.e., guinea worm disease), also have no known animal reservoirs.

As we learn more about the presence of yaws in wild, nonhuman primates, there is more and more reason to doubt the feasibility of eradication.

As we learn more about the presence of yaws in wild, nonhuman primates, there is more and more reason to doubt the feasibility of eradication. In one ethically questionable experiment described in the early 1970s, researchers demonstrated that a simian strain collected from a baboon in Guinea could indeed cause sustained infection in inoculated human volunteers.10 The entire genome sequence of this baboon strain was recently published, and it is sufficiently similar to the other T. pallidum subsp. pertenue strains sequenced thus far to be considered part of the same subspecies.11 Additionally, areas of Africa with a high prevalence of nonhuman primate infections are the same places in which yaws was once endemic in humans,12 further suggesting that strains may be circulating between humans and nonhuman primates. (See map below.)

Future studies should help clarify the relationship between human yaws-causing strains and nonhuman primate strains, and the risk of the bacterium making the jump from animals to people (or vice versa). In addition, the unique manifestations of the T. pallidum strains in East African baboons may provide a rare opportunity to identify genetic changes associated with genital infection. Is it possible that sexual transmissibility has evolved twice in T. pallidum, once in humans and once in baboons? If so, can we identify parallel genetic changes between the genomes of sexually transmitted strains in the two species? We hope that obtaining whole genome sequences from simian samples will allow us to answer some of these intriguing questions, and we are attempting to isolate new, simian laboratory strains for additional in-depth studies as well.

At the same time, skeletal investigations of ancient treponemal disease continue to forge ahead. As our knowledge of T. pallidum in both past and present populations grows, fostered by molecular techniques that yield novel data, it is possible that a combination of paleopathology, genetics, and wildlife disease ecology will yield a compelling solution to the mystery of syphilis’s origins, and a strategy to slow its spread, once and for all.

Kristin N. Harper is a health researcher at MetaMed, which offers personalized medical research services. She is interested in using population genetics to learn more about our shared past with pathogens. Molly K. Zuckerman is an assistant professor in the Department of Anthropology and Middle Eastern Cultures at Mississippi State University. George J. Armelagos is Goodrich C. White Professor of Anthropology at Emory University, Atlanta, Georgia.

© SCIBAK/ISTOCKPHOTO.COM

1492: L. PRANG & CO., BOSTON/WIKIMEDIA COMMONS; 1905: PD-LAYOUT; PD-USGOV-HHS-CDC/WIKIMEDIA COMMONS; MID-20TH CENTURY IMPERIAL WAR MUSEUM/WIKIMEDIA COMMONS; LATE 1980s: CHARLES J. SHARP/WIKIMEDIA COMMONS; 2005: CDC/DR. LYLE CONRAD; 2008: © HENDRIKDB/ISTOCKPHOTO.COM; TODAY: JOURNAL OF EMERGING INFECTIOUS DISEASES/WIKIMEDIA COMMONS

Correction (February 3, 2014): This map in this story has been updated from its original version to correctly reflect that the data on nonhuman primates come from research over the last several decades, not just the 1990s. The Scientist regrets the error.