A dozen years before the U.S. Civil War, North America was in the throes of a devastating cholera pandemic that had already claimed hundreds of thousands of lives worldwide. In Philadelphia, a physician named John Neill gathered intestines from six victims of the deadly disease, to be used for teaching purposes.
Flash forward 165 years and now one of those specimens, from an unknown male, has yielded the complete DNA of the cholera strain that was responsible for the pandemic. The find, a tour de force for modern genomics, offers new insights into the evolution of a deadly disease while underscoring the hidden value of traditional medical specimens in museum and university collections around the world.
"This research is significant because it allows us to reconstruct ancestral forms of a disease that is still with us today," said Hendrik Poinar, an evolutionary geneticist and lead researcher at McMaster University's Ancient DNA Centre in Hamilton, where the cholera genome was retrieved.
Cholera, a bacterial infection of the small intestine, is generally acquired through drinking unsanitary water. If untreated, the disease can kill its victim in as little as a day by causing severe diarrhea and dehydration. The disease is endemic in the region around the Bay of Bengal, where it is thought to have originated thousands of years ago. Maritime trade by steamship brought cholera in contact with the rest of the world in the early 1800s. Since then, there have been seven major global outbreaks of cholera, but apart from the sixth and seventh outbreak, it's not known which particular strain of the bug was behind each pandemic. Because cholera is not preserved in bones or teeth, researchers have not been able to identify and study earlier versions of the disease or trace its genetic development.
That changed after Dr. Poinar and his colleagues heard from Anna Dhody, curator of the Mütter Museum in Philadelphia, where Dr. Neill's specimens now reside. In 2008, those discussions eventually brought a team from Canada to the museum, where they painstakingly opened the lead- and wax-sealed jars containing the intestines preserved in alcohol, in hopes of extracting cholera-bearing tissue.
"You're never sure it's going to work," said Alison Devault, a PhD student at McMaster and lead author of a paper describing the find, published this week in the New England Journal of Medicine. "When you're working with one-of-a-kind samples it can be so tantalizing but it may not pan out."
In fact, only one of the six samples yielded cholera DNA, but in that case there was enough to enable the team to reassemble the microbe's entire genome. What made that goal achievable was the advent of a new technology, known as high through-put sequencing, which only became available partway through the team's analysis.
The results show that the cholera that ravaged the continent in the 1840s – killing former U.S. president James K. Polk, among many others – was an early form of what is known as the classical strain of the disease. In more recent times, another strain, called El Tor, has risen in prominence and researchers are trying to understand why. A variant of El Tor is known to have caused more than 8,000 deaths and widespread illness following a January, 2010, earthquake in Haiti.
The cholera genome the team assembled has more copies of a gene that produces the CTX toxin, which is what triggers the disease. That means the 1849 form of the classical strain may have been more deadly than the current form, though further research will be needed to fully interpret thisand other genetic differences the team uncovered. Like many pathogens, cholera has evolved through the "slow ticking clock of mutational change" as well as through the wholesale transfer of genes between strains, Dr. Poinar said. A better understanding of that evolution may eventually help researchers develop new drugs that more effectively target the disease.
"I hope this is just the beginning," said Ms. Dhody, who added that the work should encourage further examination of historic medical specimens of all kinds. "These 19th century collections can have 21st century relevance."