McMaster lab cracks genetic code for cholera outbreak in 1800's

Researchers led by the Ancient DNA Centre at McMaster University in Hamilton have mapped the genetic blueprint of the cholera bacteria responsible for a 19th-century pandemic of the disease, cracking open a veritable medical time capsule to do so.

The researchers mined a postage stamp-sized piece of tissue taken from the preserved intestine of a Philadelphia man who died of cholera in 1849.

The work confirmed the suspicion that the outbreak — the second of seven cholera pandemics in history — was caused by what is known as the classical strain of the bacterium Vibrio cholera. Currently most cholera disease is triggered by another strain — El Tor — that displaced classical as the most common cause of illness in the 1960s.

An impressive feat in its own right, this type of work should help scientists chart how pathogens like cholera emerge and change.

"It's fantastic to be able to actually study the evolution of these pathogens in real time," said Hendrik Poinar, director of the Ancient DNA Centre and senior author of the paper, which is published online this week in the New England Journal of Medicine.

"Who knows what that will allow us to look at in terms of susceptibility of these pathogens to antibiotics, whether or not there's increased or decreased toxicity to humans. So it has tremendous potential, I think, for the future of understanding how diseases evolve and then peter out in some cases — or become increasingly virulent."

One of many discoveries made by McMaster lab

The McMaster laboratory has been involved in a number of impressive discoveries in the emerging field of paleopathogenomics, the excavation of the genetic sequences of pathogens that infected in eras before science could detect and identify them.

For instance, the lab was a part of a team that recovered the DNA of Yersinia pestis — the plague — from the teeth of skeletons in a mass grave in London. That work led to the sequencing of the blueprint for the pathogen responsible for the mid-13th-century pandemic known as the Black Death, which wiped out an estimated 60 per cent of the population of Europe at the time.

Poinar admitted that after the publication of the Black Death paper in 2011, he and his research team wondered: "Well, if we can really travel back in time and we're very interested in the evolution of infectious diseases, then what are other things that we have access to that we could really look at that are not only interesting from a historical perspective, but interesting because they're pressing in terms of the present day?"

They thought of cholera, a bacteria spread in contaminated water that killed enormous numbers of people in the past and still claims between 100,000 and 120,000 lives a year, according to the World Health Organization.

It is known that El Tor was responsible for two cholera pandemics in the 20th century. But the cause of the five pandemics in the 1800s was pure speculation. Ancient DNA could answer that question.

Poinar and his team immediately knew there was one major hitch. Where some pathogens leave traces of their presence in the bones, the core of the teeth or even hair follicles, cholera is only found in the gastrointestinal system. And organs like the intestines decay far faster than the skeleton. They would not find an intestine to test if they dug up the grave of someone who died from cholera in the first half of the 1800s.

Cholera sample came from Philadelphia

But they recognized there was another option: jars of preserved tissues in many museums and universities around the world. These relics of a bygone era are unrecognized treasure troves for researchers with the interest and capacity to retrieve the DNA from the preserved tissues, Poinar suggested.

"There are remarkable sets of archival medical collections around the globe, many of which are protected, I would say, by professors that are in late retirement ... that have been trying to keep their collections from doom and gloom by the universities always looking for spaces for new incoming faculty," he said.

"When we see these collections we say, 'Oh, my Lord, do you know how much DNA is buried within there and how much we can actually discern about the infectious diseases of the past?"'

One such collection is held at Philadelphia's Mutter Museum, established by the College of Physicians of Philadelphia in 1858. It had several preserved intestines from people thought to have died during the second of the cholera pandemics, which dated from 1829 to 1849.

The museum agreed to let the researchers have small pieces of three, which all tested positive for cholera. The DNA sequence was recovered from one.

1849 strain more severe

The sequence reveals the classical strain was the infecting agent. It is similar to the contemporary classical cholera strain but is missing three large genomic "islands" — groups of genes — found in its modern descendants. The acquisition of those additional gene groups may explain why the classical strain began to wane in the 20th century, Poinar said.

The 1849 version also looks as if it would generate more cholera toxin, which may mean the classical strain caused more severe disease back then.

This work will open up new research possibilities for scientists studying cholera, said Anne Stone, an evolutionary anthropologist at Arizona State University in Tempe. Stone was not involved in this project but works in this field, looking for tuberculosis in bones recovered from archeological sites.

"What's really lovely about the whole genome studies is that you can look at the evolution of the pathogen and how it's changed over time and hopefully make inferences or generate sensible hypotheses about why a pathogen was maybe more virulent, or had some different effect than it does today," Stone said.

The work was funded by the Natural Sciences and Engineering Research Council, the Social Sciences and Humanities Research Council, an NHMRC Australia Fellowship and an Ontario Graduate Scholarship.