The world is in the grip of its seventh cholera pandemic, but that’s not exactly news. Today’s pandemic has been around since the 1960s, burning through developing countries like Democratic Republic of Congo and Haiti. Now, scientists have used DNA from historical samples to figure out how the modern strain—responsible for 1304 deaths last year alone—morphed from a harmless microbe centuries ago into a deadly pathogen today.
Cholera, caused by the bacterium Vibrio cholerae, produces watery diarrhea that can lead to dehydration and death. Because Vibrio spreads through contact with raw sewage, it thrives in regions lacking clean water or modern sanitation. With proper treatment, mortality is low, but the deadly bacterium’s ability to spread rapidly has kept it at the forefront of global public health efforts.
To find out how the current pandemic got its start, scientists looked at DNA from preserved cholera samples in laboratories around the world. In the same way scientists create evolutionary trees, the researchers made a branching map of relationships between strains through time using genetic comparisons. Combining their analysis with written accounts of old outbreaks, the team defined six stages in the evolution of the modern strain that led to its toxicity and its ability to spread, they report this week in the Proceedings of the National Academy of Sciences.
Strain No. 7 diverged from its relatives, 1–6, around the turn of the 18th century, says paper author Peter Reeves, a microbiologist at the School of Life and Environmental Sciences at the University of Sydney in Australia. But that’s just an estimate: The first observation of the new lineage comes from a laboratory in El Tor, Egypt, in 1897. By that time, the “El Tor” strain differed from its relatives by about 30%, but it didn’t spread rapidly and it didn’t make people sick.
The next decade was pivotal for the bacterium’s evolution. It bounced around the Middle East, picking up a key gene called tcpA, which encodes a hairlike structure on its surface that clings to the wall of the small intestine. This change alone didn’t make the strain pathogenic, but it may have helped it live longer in the guts of religious pilgrims traveling to and from Mecca. Then, sometime between 1903 and 1908, the El Tor strain picked up a crucial piece of hitchhiking DNA that likely triggered its ability to cause disease in humans.
At the time, the sixth cholera pandemic was in full swing in the Middle East, Europe, and North Africa. Reeves says that a phage—a virus that infects bacteria—picked up the “classic” form of the cholera toxin gene from the sixth strain and then infected the El Tor strain, transferring the toxin gene. The new trait would have caused watery diarrhea, accelerating the disease’s spread through the water supply. But it was still missing the key genes it would need before it could cause a full-blown pandemic.
From there, the strain moved east to Makassar, Indonesia. There, it gained new genes that likely increased transmissibility, along with the two “islands” of DNA used to identify it as unique today, Vibrio seventh pandemic (VSP) 1 and 2. However, Reeves says there’s very little evidence that the VSP islands did much, if anything, to help the bacteria spread. In fact, the researchers are still unsure which changes drove the increase in transmissibility from 1925 until 1961, when the disease spread around the rest of the world.
To find out which changes accelerated the organism to pandemic levels, we would have to do human testing, says Reeves, infecting a large group with different strains to see how fast it spreads. “If we can understand what was happening in this pandemic strain, it might help us make predictions about whether any of the other ones have the potential,” he says. But, “of course you can’t do that as an experiment.”
Given the information available, “this is a perfectly fine study,” says Edward Ryan, a microbiologist at Harvard University who was not involved in the new work. “It tells a coherent story that is very biologically plausible.”
But it misses a big part of the picture, says microbiologist Mark Achtman at the University of Warwick in Coventry, England. “I am skeptical about the completeness of the evolutionary story when it is based exclusively on the remnants of human disease isolates.” Achtman says that analyses limited to human samples are lacking because they don’t examine the cholera always circulating in the environment, outside human hosts. At any point in history, he says, new strains could have arisen from these pathogens rather than from human-to-human transmission.
But that would be extremely tough to nail down, Ryan says. Few historical environmental samples exist, and evidence that such strains made the jump to humans is even harder to come by. “Were there other strains in other areas of the world that weren’t collected that might give a more complete story?” Ryan asks. “Yes,” he says. “But at the end of the day … [this] is a reasonable biological story based on the best available data of how a pathogen emerges historically and came to dominate.”