Today, our most fearsome natural enemies aren't big, fierce animals. They're microscopic invaders, with names like O104:H4. Their weapon is evolution.

O104:H4 is the label given to the strain of E. coli responsible for the food-borne outbreak currently sweeping through Europe. The organism is so good at infecting us that a deadly case could start with just 10 to 50 cells. Once ingested, this new E. coli multiplies into the billions, using various tricks to evade the immune system.

A benign form of E. coli inhabits all of us, but unlike these friendly bacteria, the new strain forms clumps that adhere to human intestines, where it secretes a deadly substance called Shiga toxin. In the worst cases, the toxin invades the bloodstream, where it massacres blood cells and eventually destroys the kidneys.

In those cases, antibiotics may actually kill a patient by stimulating the bacteria to release even more toxin.

As of Friday, the outbreak had sickened more than 2,700 people across 13 countries and killed 29. Last week, scientists traced the outbreak to infected bean sprouts, which they had implicated once before and rejected. If it stands, that still leaves many questions about where this new bacteria came from and how it contaminated the sprouts. Uncovering its evolutionary story could lead to quicker diagnostic tests and strategies for preventing deadly outbreaks in the future.

Though Darwin postulated that evolution happens through slow, gradual change, the evolution of E. coli into a killer can happen overnight. "They're constantly evolving and we have to catch up," said Chitrita "Chobi" DebRoy, director of the E. coli Reference Center at Pennsylvania State University.

Scientists say understanding how these bacteria evolve might lead to new ideas for stemming the current outbreak and preventing future ones.

In this case, E. coli "has taken a turn nobody expected."

O104:H4 is part of a family known as the enteroaggregative E. coli, because they're sticky, binding like glue to each other and to surfaces, including human intestines. DebRoy says these bacteria are associated with persistent diarrhea afflicting children in developing countries. Until now, U.S. agriculture officials didn't pay much attention to them.

That is, until one was found that also creates Shiga toxin. It's the toxin that kills patients, not the infection itself, so even destroying the bacteria with antibiotics can't save some patients. Life or death for victims hinges on whether they get too much toxin for their bodies to handle.

It's the same toxin that's been associated with several previous outbreaks, including the one that was spread on California spinach several years ago. That strain, labeled O157:H7, did not have the sticky, aggregating property that characterizes 0104:H4.

Somewhere it acquired two dangerous sets of genes absent in benign strains.

The E. coli don't acquire these new genes by waiting for random mutations to produce them. Instead, they got them by swapping genetic material across different strains, sometimes across bacterial species, thereby gathering whole new traits all at once.

"It's a fascinating organism because it has the ability to pick up new genes from other organisms and evolve into a variety of types," said Edward Dudley, a Penn State assistant professor of food science. "It's like they're playing a game of poker and shuffling cards back and forth and somebody comes up with a jackpot hand that allows it to become something nasty."

Bacteria shuffle the cards in several ways. One way is something called conjugation, in which one bacterial cell sticks a strawlike organ called a pilus into another cell, and the two transfer pieces of genetic code. The process is considered a bacterial equivalent of sex.

In the case of O104:H4, however, the bacteria appear to have acquired new genetic material from a type of virus - a phage.

Phages are viruses that invade bacteria, carrying stretches of DNA that get incorporated into bacterial genetic code. Some of the time phages just coexist with their hosts - "The phages become part of the bacteria's DNA," Dudley said. "They divide when the bacteria divide."

But then, if the bacteria become stressed, phages can sense this, he said. Then they break out of their hosts and go on to infect new ones.

The combination of two genes that enable E. coli to produce Shiga toxin is carried by such phages. "That's really a major way organisms evolve new traits," he said.

The scientists aren't sure if the bacteria derive any benefit from producing the Shiga toxin genes. It's rarely advantageous for bacteria to kill their hosts. In the earlier spinach outbreak, of O1057:H7, scientists found the bacteria were adapted to live in cattle, which are not sickened by the toxin.

The new E. coli, O104:H4, may, too, gain some advantage in cattle or some other animal host. "It certainly didn't evolve to make humans sick," Dudley said. Some have suggested the toxin can protect the bacteria from being eaten by amoebas, but that's just a guess at this point.

Around the world, scientists are trying to find out whether this new strain, too, is being incubated by cattle, in which case the bacteria can enter the food chain when manure from those cattle gets into irrigation water or otherwise finds its way onto crops.

Health authorities have blamed cucumbers, tomatoes, lettuce, and, most recently, bean sprouts.

Last week the BGI, formerly the Beijing Genomics Institute, released the full genetic code for O104:H4. That may offer new clues. Researchers are also taking advantage of samples of 70,000 strains of E. coli at Penn State - the largest such repository in the country. "We've been collecting strains for the last 50 years," said DebRoy. That history enables scientists to trace patterns of E. coli evolution through the decades, she said.

When they examine the genetic material in any E. coli, what they find is a patchwork of genes from other bacteria, said biologist David Sanders of Purdue University.

"What we see in these genomes is they are incredibly mosaic," he said. The stretches of DNA that get traded through phages or more direct swaps are called mobile genetic elements, he said, and they allow a fast, continual evolution of new strains.

Those jumping genes have also enabled other bacteria to become resistant to antibiotics, he said, due mostly to the use of these drugs in farm animals.

While scientists haven't identified an animal carrier yet, environmental microbiologist Jennifer Clancy suspects it's cattle. The fact that the cattle don't get sick makes it even harder for authorities to track down the source of this outbreak, said Clancy, who works for the California-based engineering firm Tetra Tech.

On the other hand, said Penn State's Dudley, cattle have never been known to carry this aggregating type of E. coli before. He said it's possible O104:H4 evolved in human hosts.

And yet in humans, it's not only highly virulent, it also has what's called a low infectious dose, meaning exposure to just a few bacterial cells, or perhaps a single one, could cause illness.

Scientists can't say for sure whether this is a freak incident or part of a trend spawned by modern farming practices. Penn State's Dudley says this is a crucial question for the scientists. "Was this due to some event that may not happen for another 30 years, or never again, or has something changed about the way we raise our food?"

Understanding the evolution of deadly E. coli could help people avoid being caught by surprise in the future, he said. There are other Shiga toxin-producing bacteria out there that are not nearly as dangerous as this one or the one that contaminated California spinach.

"There's something special about these groups to be able to cause so much disease in humans," he said. It all comes back to that deadly poker game. "We want to know exactly what cards a bacteria like this needs to be holding."

Contact staff writer Faye Flam at 215-854-4977 or
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