THE BACTERIA IN THE DISH on my desk are a long way from home. Their ancestors left the body of a diphtheria patient in California eighty-five years ago and have never returned to another human gut. They were transported into another dimension—of flasks and freezers, centrifuges and X-rays. These laboratory creatures have enjoyed a strange comfort, gorging themselves on amino acids and sugar. And over hundreds of thousands of generations they have evolved. They have become fast breeders and have lost the ability to survive for long in the human gut. They avoid extinction only because they have become so dear to the biologists who carry them from flask to freezer to incubator.
Over those eighty-five years their wild cousins have gone on with their own lives. They have continued to colonize guts, and they have evolved as well. The microbes that live inside us today are not the same as the ones that lived inside people in 1920. We are the source of much of that change.
The most obvious way we have changed E. coli is by trying to fight infections with drugs. E. coli and other bacteria have responded to those drugs with a rapid burst of evolution. They can now resist drugs that once would have wiped them out. Scientists are now left scrambling to find new drugs to replace the failed ones, and there's little reason to think E. coli and other microbes won't evolve resistance to them as well.
While some scientists have observed E. coli evolve in their laboratories, we have also launched a global, unplanned experiment in E. coli evolution. Like laboratory experiments, the rise of resistant E. coli is offering its own clues to the workings of evolution. Resistance can evolve through the familiar course of random mutations and natural selection. But in some ways, E. coli is not fitting into the conventional picture. In the evolution of resistant E. coli, some researchers claim to have found evidence that the microbe can alter the way it mutates to suit the conditions it faces. And while Darwin erected his theory on the idea that organisms inherit traits from their direct ancestors, E. coli has acquired much of its resistance to antibiotics from other species of bacteria, which can trade genes like business cards. These discoveries are significant not only because they may help in the battle against drug-resistant pathogens. They may also reveal forces that have been shaping life for the past 4 billion years.
The era of antibiotics began suddenly, but it followed a long, slow prelude. Traditional healers long knew that mold could heal wounds. In 1877, Louis Pasteur found that he could halt the spread of anthrax-causing bacteria by introducing "common bacteria" in their midst. No one knew what the common bacteria did to stop the anthrax, but scientists gave it a name anyway: antibiosis, the ability of one creature to kill another.
In 1928, Alexander Fleming, a Scottish bacteriologist, discovered a molecule that could kill bacteria. He noticed that one of his petri dishes had become contaminated with mold. There were no bacteria near it. He ran tests on the mold and discovered that it could halt the spread of bacteria. Yet it did not harm human cells. Fleming isolated the mold's antibiotic and named it penicillin.
At first, penicillin did not look like a promising drug. For one thing, Fleming could extract only tiny amounts of it from mold, and it proved too fragile to be stored for very long. It took ten years for penicillin to live up to its promise. Howard Florey and Ernst Chain at Oxford University figured out how to coax the mold to make enough penicillin to test on mice. They infected mice with streptococci and injected some with penicillin. The treated mice all survived, and the others all died. In 1941, Florey and Chain persuaded American pharmaceutical companies to adopt their penicillin production scheme and expand it to an industrial scale. By 1944, wounded Allied soldiers were being cured of infections that would have killed them a year before. In the next few years, a rush of other antibiotics came along, mostly derived from fungi and bacteria.
Antibiotics, scientists discovered, kill bacteria in many ways. Some attack enzymes that help replicate DNA. Others, such as penicillin, interfere with the construction of the peptidoglycan mesh that wraps around E. coli and other bacteria. Gaps in the mesh form, and the high-pressure innards of the microbes burst out. Organisms naturally make only trace amounts of antibiotics, but drug companies began to produce them in enormous bulk, rearing fungi and bacteria in giant fermenters or synthesizing drugs from scratch. It would take billions of microbes to produce the antibiotics in a single pill. In such a concentrated form, antibiotics had a staggering effect on disease-causing bacteria. They didn't just reduce infections. They got rid of them altogether, and with few noticeable side effects. The war against infectious diseases seemed to have suddenly become a rout.
But even in those heady days of early victory, there were signs of trouble. At one point in their research, Florey and Chain discovered that their cultures of mold had been invaded by E. coli. The bacteria were able to survive in a soup of penicillin by producing an enzyme that could cut the antibiotic molecule into feeble fragments.
As penicillin was being introduced to the world, microbiologists were discovering how mutations arose in E. coli. In 1943, Delbrück and Luria showed that mutations spontaneously made E. coli resistant to viruses. In 1948, the Yugoslavian-born geneticist Milislav Demerec showed that the same held true for antibiotics. He bred resistant strains of E. coli and Staphylococcus aureus. Both species became increasingly resistant as they picked up a series of mutations. In the same year that Demerec published his results, doctors reported that penicillin was beginning to fail in their Staphylococcus-infected patients.
These disturbing discoveries did nothing to halt the rise of antibiotics. Today the world consumes more than ten thousand tons of antibiotics a year. Some of those drugs save lives, but a lot of them are wasted. Two-thirds of all the prescriptions that doctors hand out for antibiotics are useless. Antibiotics can't kill viruses, for instance. Many farmers today practically drown their animals with antibiotics because the drugs somehow make the animals grow bigger. But the cost of the antibiotics is greater than the profit from the extra meat.
Along with the rise in antibiotics has come a rise in antibiotic resistance. Drugs that were once fatal to bacteria are now useless. E. coli's story is typical. Resistant strains of E. coli first emerged in the 1950s. At first only a small fraction of E. coli could withstand any particular antibiotic, but over several years resistant microbes became more common. Soon the majority of E. coli could withstand the drug. As one drug faltered, doctors would prescribe another—a stronger drug with harsher side effects or a more recently discovered molecule. And in a few years that drug would begin to fail as well. Before long, strains of E. coli emerged that could resist many antibiotics at once.
E. coli uses many tricks to dodge antibiotics. As Florey and Chain discovered, it can secrete enzymes that cut penicillin into harmless fragments. In some cases, E. coli's proteins have taken on new shapes that make it difficult for antibiotics to grab them. And in other cases, E. coli uses special pumps to hurl antibiotics out of its interior. For every magic bullet science has found for E. coli, E. coli has acquired an equally magic shield.
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