While COVID-19 gets most of the headlines in the United States, much of the world is simultaneously in the grip of different pandemic: cholera.
That waterborne disease is caused by bacteria, not viruses, but the two microbes share some big-picture traits. Human behavior is largely to blame for their spread. New strains come and go. And often it is not immediately clear why.
That type of mystery is what drew a team of scientists recently to Philadelphia’s Mütter Museum, which owns an unusual set of relics from the cholera pandemic of the mid-1800s: pieces of intestines from six people who died of the disease. DNA analysis of one of the samples yielded new insight into how one strain of bacteria can overtake another, the researchers reported in a new study.
Broadly speaking, the authors found that the current strain of cholera-causing bacteria, called El Tor, became dominant by “outcompeting” its predecessors — much like the omicron variant of the coronavirus evolved a competitive edge to crowd out previous strains.
But the similarities end there. Whereas omicron’s edge seems to involve greater transmissibility, among other factors, cholera’s brand of competition consists of direct warfare. In addition to secreting toxins that make people sick, resulting in severe diarrhea, the bacteria secrete toxins that attack other types of bacteria, said Stefan Pukatzki, a senior author of the study and a microbiologist at City College of New York.
“It’s a little nanomachine that injects toxins into neighboring bacteria,” he said.
But when they analyzed DNA from one of the Mütter Museum’s samples, dated to 1849, the researchers found that the code for this weapon, though present, was modified so it could not function. The authors also analyzed a sample of cholera-causing bacteria from 1965, and found that it, too, had a disabled “nanomachine.”
Though they lacked this capacity for direct warfare, those earlier strains, in their day, somehow became dominant for other reasons. But when El Tor came along in the 1960s with the ability to fight, it displaced earlier strains, the authors concluded.
The authors hope that these genetic clues could provide a road map to possible treatments. Relative to its predecessors, El Tor causes milder symptoms in humans (as omicron seems to do, relative to earlier coronavirus strains), but it still can be deadly. In countries with poor access to clean water and sanitation, cholera kills through a combination of severe dehydration and disrupting the person’s electrolyte balance.
In Nigeria, for example, cholera has killed twice as many people as COVID in 2021, according to the nation’s health ministry.
The success of the Mütter research depended on a bit of luck and on the foresight of a 19th-century Philadelphia physician who was determined to learn how the disease wreaked such havoc, according to museum curator Anna Dhody, a coauthor of the study in Nature Communications.
The first hurdle: The bacteria that cause cholera are found only in “soft tissues,” primarily the intestines — not in bone.
“Your gut, when you die, is one of the first things that decomposes,” she said. “You’ve got to get it out quick and preserve it, or it’s gone.”
As a result, 19th-century samples of intestines are rare, particularly those from cholera patients. But this is the Mütter Museum, after all. Where else would a 21st-century scientist turn in search of weird, old body parts?
The collection includes six samples of choleric intestines from 1849, collected by John Neill, a Philadelphia physician who treated cholera patients during the city’s outbreak. Records suggest he examined the samples under a microscope in hopes of discovering how the disease came about, though without much success, Dhody said.
Physicians at the time generally blamed the disease on “miasma” — poisonous vapors. Bacteria would not be conclusively identified as the culprit for decades.
The second hurdle for the modern-day researchers was obtaining viable DNA. For much of the 20th century, museums stored perishable specimens in a solution of formaldehyde, which degrades the genetic material — not that anyone knew what DNA was until the 1950s, much less how to decipher it. But Neill’s specimens are so old they predate the widespread use of formaldehyde. Instead, he stored them in alcohol, which turns out to preserve DNA fairly well.
What’s more, he sealed his specimen jars with extreme zeal. Several of the jars had pieces of pig’s bladder stretched across the top, covered by a lead disk, and finally with a layer of parchment coated in a black, pitch-like material.
“He managed to preserve them so well that when I found them in 2007, the jars were still completely full of alcohol,” Dhody said.
The intact, original seals gave scientists confidence that the samples inside would not be contaminated by modern DNA from other organisms.
Pukatzki was part of a team that discovered El Tor’s “nanomachine” more than a decade ago, when he was at Harvard. But until the new study, no one knew whether previous strains had the same capacity.
The piece of intestine from 1849 that he used in the new analysis underwent genetic testing once before, as described in a 2014 study. On that occasion, scientists identified the strain of bacteria and also learned that the patient was of African ancestry.
It is likely Neill obtained the sample without seeking the family’s consent, as was common practice in the 19th century, Dhody said. That particular sample is not on display, but the museum’s glass-fronted cases contain plenty of other human remains for which no names or details about consent are known. The museum recently updated its signage to explain how ethical standards have evolved.
The availability of the samples represents an invaluable service to science and medicine, Pukatzki said. While Neill did not discover the secrets of cholera with his microscope, his samples have allowed his modern-day counterparts to do so.
“Giving people like me a chance to go back in time,” Pukatzki said, “is just tremendous.”