Whose disease? Genomes help to resolve the mystery of the pox

A new report in the snappily titled journal PLOS Neglected Tropical Diseases presents, for the first time, the sequenced and reconstructed genomes of historic Treponema pallidum subspecies – the bacteria responsible for syphilis and three other related diseases. This promises to help solve the mystery of the origin of one of humanity’s most feared diseases.

Syphilis is a gruesome malady. The causative agent, a corkscrew shaped bacterium, is sexually transmitted. It initially produces pustules which turn to ulcers, then a raft of other symptoms in its secondary phase, most notably a widespread and unsightly rash of varying severity.

In its tertiary stage, which can appear many years after initial infection, it can produce gross deformations of flesh and bone, or attack the central nervous system or heart. It can also be passed from mother to unborn child.

The variety of symptoms syphilis can present has led to the disease being known as the Great Imitator, as it can masquerade as a host of other illnesses and is often therefore misdiagnosed.

But it was not always thus. The modern disease is a very different beast than the monstrosity which first appeared in Europe at the end of the fifteenth century.

In 1494 the French King Charles VIII entered Italy bent on invading the city of Naples. The Italian Crown was in debt to the papacy, and Pope Innocent VIII convinced Charles to act as a debt recovery agent. Charles and his 25,000 strong army entered Rome and as one paper puts it “for one month … led a life of limitless depravity”.

In February 1495, the army took Naples and indulged in what the famous medical historian Roy Porter called, “the usual orgy of rape and pillage.”

Soon a new epidemic was on the rise. Sufferers erupted in genital sores and pustules from head to knees that ate into bones an caused tumour-like disfigurations, as well as making the flesh to fall away from the face, eroding nose and lips.

It was excruciatingly painful and often fatal.

One contemporary victim, Joseph Gruenspeck, described it as “a disease which is so cruel, so distressing, so appalling that until now nothing so horrifying, nothing more terrible or disgusting, has ever been known on this earth.” Thanks to the recently invented printing press, the disease gained much attention as physicians published their accounts, such as this from a French doctor in 1495: “So repulsive is the appearance of the whole body, so great is the agony, above all at night, that this malady surpasses in horror both leprosy and elephantiasis and threatens a man’s life.”

It was also highly virulent.

As one historian has noted, in 1495 the disease crossed the Alps and by January 1496 it was reported in France and Switzerland. Within months it was all over Holland and Germany. It took England in 1497 and headed into Eastern Europe by 1499.

And the peoples of Western Europe blamed each other for this new scourge. The French called it the ‘disease of Naples’, while the Neapolitans called it the ‘French itch’. The Dutch, the Danish, the Portuguese and the people of North Africa named it the ‘Spanish disease’, the Russians dubbed it the ‘Polish disease’, the Polish termed it the ‘German disease’, the Siberians hailed it as the ‘Russian disease’, the Turkish called it the ‘Christian disease’, and the Italians, Germans and British all referred to it as the ‘French disease’.

Someone else was always to blame.

Soon a new name came to the fore: ‘the pox’.

Over time the symptoms of the disease modified, and by 1546 it had evolved into its modern form, presumably because Treponema pallidum evolved to keep its host alive longer in order to increase infection rates.

In 1905 a German parasitologist first identified the bacteria under the microscope, and in 1943 researchers discovered that penicillin could effectively treat the disease, putting an end to the tyranny of the pox.

It did not go unremarked upon at the time that this new disease seemed to have appeared so soon after Christopher Columbus’s return from the New World, and many thought it was the price to pay for conquest.

The discovery of a new treatment for the pox in the form of the bark of a tree from South America, as the medical historian William Bynum has noted, “reinforced the notion that syphilis had come from the New World, the assumption being that God placed remedies near to the origins of diseases, to encourage us to look for them.”

However, modern science is still debating exactly where syphilis originated, with two theories being dominant: the Columbian and the pre-Colombian hypotheses.

The first suggests that, along with people, culture, plants and animals, diseases were also part of the ‘Columbian exchange’, with Europeans introducing dysentery, malaria and smallpox to the New World, and receiving syphilis by way of thanks. This suggests that syphilis originated in the New World and was returned to Europe by Columbus.

The pre-Colombian hypothesis argues that syphilis was already present in Europe (and elsewhere) and coincidentally underwent various mutations that saw an increase in virulence and the aggressiveness of symptoms during the late fifteenth century.

The authors of the current paper, led by Johannes Krause of the Max Planck Institute for the Science of Human History in Jena, Germany, suggest that genetic and archaeological evidence exists to support both hypotheses. This has led to intense debate and the ongoing mystery of the origins of syphilis.

Part of the problem is that it is near impossible to tell the various diseases caused by T. pallidum subspecies, known as ‘treponemal diseases’, apart.

As a 2014 paper puts it, “the four members of the bacterial family cannot be differentiated with morphological, chemical or immunological methods.” Beyond this, write the authors “even in modern patients with advanced stage syphilis… molecular detection of the bacterium is challenging.”

What evidence there is mainly comes from the analysis of skeletal remains of historic victims of treponemal diseases, along with the study of modern treponemal genomes. This lack of evidence has made it a daunting task to reconstruct the evolutionary history of T. pallidum.

Krause and his team, however, may have made a breakthrough. In the 1990s an archaeological excavation of the site of the Franciscan Convent of Santa Isabel in Mexico City revealed the remains of 239 individuals. Krause and his colleagues discovered the remains of five displaying skeletal symptoms of T. pallidum infection, three of which tested positive for treponemal DNA.

The team were able to extract this DNA, and for the first time sequence and reconstruct three historic T. pallidum genomes: two from T. pallidum ssp. pallidum (responsible for syphilis) and one from T. pallidum ssp. pertenue (responsible for a related disease, yaws). Dismayingly, their findings indicate that the different treponemal diseases have remarkably similar symptoms in historic remains, rendering much of the evidence derived from skeletal analysis suspect.

However, the very fact of the recovery and sequencing of this historic DNA is a breakthrough in itself.

“Our study demonstrates the possibility of retrieving ancient T. pallidum genomes from archeological material,” say the authors, “and thereby establishes a new method that could greatly contribute to uncover the mystery regarding the origins of treponemal diseases.”