All it took for flesh-eating bacteria to go from harmless organisms to gruesome infectious pathogens was four mutations and about 35 years. That's what an international group of researchers announced today in a study that outside experts are calling the largest bacterial genome paper ever published.

"One of the major proteins is an active ingredient in Adolphe's meat tenderizer."

Despite its name, flesh-eating bacteria — a type of streptococcus — doesn't consume flesh. What it does do is produce proteins that break down human skin, fat, and muscle — a process that causes flesh to die rather quickly. "One of the major proteins is an active ingredient in Adolph's meat tenderizer," says James Musser, an infectious disease expert at Houston Methodist Research Institute and co-author of the study published today in Proceedings of the National Academy of Sciences. The ensuing disease, called necrotizing fasciitis, is very difficult to treat; although antibiotics can do the trick, skin-grafting and amputations are not uncommon. Worse yet, the disease causes death in 70 percent of cases if left untreated. And the infection is actually human-specific, so other animals can't get the disease. These characteristics, Musser says, make it a particularly interesting beast with which to work.

To find out how the bacteria mutated, the researchers analyzed the genomes of over 3,615 population-based strains of streptococcus. For the most part, these organisms don't make humans sick, but some can result in pink eye, meningitis and pneumonia. The most notorious strep strain, however, is probably Group A streptococcus — the group that tends to cause the most epidemics of flesh-eating disease. "We needed this magnitude of data," Musser says, "to be clear about what transpired to create this thug pathogen."

"there were four key genetic changes."

Once the researchers had gathered all the historical genomic data, they set about building a molecular clock where each change in the bacterial genome brought them closer to finding out exactly what genetic changes allowed the pathogen to become this successful. "By working backward, we were able to determine that there were four key genetic changes," Musser says. The first two mutations — changes that took place prior to 1960 — arose after a single progenitor cell line became infected with two different types of viruses. "Bacteria can get viral infections too," Musser says, "and the viruses that they got infected with carried genes encoding novel toxins," which the bacteria were then able to integrate into their own DNA.

The third mutation involved a change in a single nucleotide — nucleotides are subunits of DNA and RNA — that Musser says allowed the bacteria to produce a better toxin than the one that previously existed. "It was just a change in one amino acid in the toxin around the 1960s or 1970s," Musser says. Finally, the last mutation event was gene transfer with another bacterium that took place around 1983. And according to Musser, it gave the bacteria the ability to encode two cell-killing toxins in far greater quantities that they could before. "The whole game that the organism plays is to figure out how to make more toxins or how to make them in increasing amounts." Flesh-eating bacteria actually produce over 90 different types of toxins, Musser says, but this combination of four mutations is what makes them particularly devastating.

A single progenitor cell line

Yet what's most surprising about the study's results, Musser says, is that all four mutations occurred in a single progenitor cell line — no other cell line mutated in this way. "Over time, there was a cell that sequentially acquired these various additional parts so that at the end of the day, when it acquired that fourth event, it created that souped-up streptococcus." Musser equates this to one super-customized car, where sequentially adding a new engine, exhaust, and sound-system eventually makes it stand out like no other.

"A new strain of strep will emerge in 35 years from 1987."

Now, Musser's team is delving even deeper into the origins of flesh-eating bacteria. He says that researchers still need to know precisely why this organism spread so rapidly, and globally. Yet, that these scientists were able to construct such a detailed mutation timeline is pretty remarkable, says David Morens, an epidemiologist at the National Institutes of Health who did not participate in the study. "Nothing like this has ever been done before," he says. "This is a pathogenic organism that evolved from something that wasn't pathogenic, and then morphed into something extremely infectious — and now we know how it happened." Morens says this study won't help anyone cure disease, but it will help in surveillance because "now we know which steps are bad."

Patrick Schlievert, a microbiologist at the University of Iowa who co-authored the first paper to describe flesh-eating bacteria in 1987, agrees with Morens. He told The Verge that Musser's study shows that future mutations will depend on gene movement by viruses, and that they will occur along the same timeline as they did with flesh-eating bacteria. "I will tell you that a new strain of strep will emerge in 35 years from 1987," he wrote, "but I cannot tell you what it will look like or where it will begin... just that it will happen." If scientists are to stop the emergence of super-successful pathogens, Schlievert said, they will have to find a way to halt those viruses from spreading. Perhaps then, "they might be able to stop these epidemics."