In 2005 and 2006, 53 patients who checked into a rural South Africa hospital turned out to be infected with extensively drug-resistant tuberculosis (XDR TB). The bacterium proved impervious to antibiotics, ultimately killing 52 of the patients.

This outbreak in Tugela Ferry, KwaZulu-Natal province, was the largest ever reported for XDR TB—and the primary strain involved currently accounts for nearly 80 percent of such infections in the province. New research finally tells the full story of the deadly strain's origin. As reported last October in the Proceedings of the National Academy of Sciences USA, it in fact emerged 250 miles away, more than a decade before the first recorded case. The researchers behind the paper say the multidisciplinary tool set they used to find its origin could help identify other drug-resistant pathogens early, as they emerge, and stop them from spreading.

“The bottom line is that this strain, like many other pathogens, took time to build,” says Barun Mathema, an epidemiologist at Columbia University and the paper's senior author. “But if you have your eye on the ball, you can pick up on these mutations and take action.”

Mathema and his colleagues sequenced more than 300 TB genomes from patients infected in KwaZulu-Natal, mostly from 2011 to 2014, and found 78 percent of the samples were genetically related to the Tugela Ferry strain. Phylogenetic reconstruction (a statistical method used to infer evolutionary history) revealed when the strain's mutations appeared and expanded, and the scientists built 3-D models of the bacterium's protein structures to find how each mutation helped the pathogen build resistance and adapt. They learned the strain had acquired three important and unusual mutations, the first in the early 1980s and the last around 1993. In the mid-1990s South Africa's HIV epidemic—which created a population with compromised immune systems—helped the strain to spread. The researchers looked at the samples' geographical distribution from associated GPS data and used population genetics and geospatial modeling to determine how genetic changes propagated from place to place. They found that the strain originated far from Tugela Ferry and migrated via popular travel routes. “All these factors came together to make this an explosive outbreak,” Mathema says.

Drug resistance is a growing problem worldwide. Mathema adds that applying whole-genome sequencing in real time to samples taken from patients, combined with a multipronged analytical approach akin to the one applied here, could help researchers detect worrying mutations before they become emergencies. Public health agencies in London, New York City, and elsewhere already do whole-genome sequencing on a small scale—but a lack of funding, expertise and capacity presents obstacles for expanding this vision.

“A lot of people in the field agree that this is where things should go,” says Maha Farhat, a biomedical informatics researcher at Harvard Medical School and pulmonary and critical care physician, who was not involved in the research. “But that would involve public health agencies investing in these tools.”