Dirty war: hostile terrain conceals enemies' secrets

December 7, 2007

The battle to defeat infections should look to the soil and the sea, where microbes flourish in conditions every bit as harsh as the human gut, writes Geoff Watts. With hospital-acquired infections and antibiotic resistance providing headaches for politicians and headlines for journalists, microbiology has endured a less-than-welcome prominence in the past year or two. But while rows about over-prescribing and hospital cleaning have dominated public discourse, biologists have been continuing to tackle more fundamental issues in the natural history of microbes. And some have found unexpected answers in unlikely places: the sea and the soil. It is these environments that seem to have conspired over time to give the microbes what they need to flourish at our expense.

Vast numbers of bacteria, for example, thrive naturally in the gut; but where did they originally acquire the capability to live in such an apparently unpromising environment? Quite possibly, in some cases, from the sea. Likewise, the many species that form our internal menagerie have a seemingly inexhaustible repertoire of defensive chemical tricks for coping with whatever the drug industry can throw at them. The continuing source of this talent for survival? Quite probably, the soil.

First, then, to where everything begins - the ocean. A benign milieu, you may think. A nurturing environment conducive to life and quite unlike the interior of the gut, with its high acidity, perpetual darkness, negligible oxygen and swiftly fluctuating chemistry. These conditions do not, however, prevent Helicobacter pylori , the organism that can trigger gut ulcers and gastric cancer, from establishing itself in about half the human population. Nor have they deterred various strains of Campylobacter , a common cause of food-borne diarrhoea, from setting up home in the intestine. But how could the sea ever have prepared these two microbes to cope with such an arduous existence?

One clue lies in a couple of other members of the same class of bacteria. These live not in the human gut but in some of the less salubrious regions of the deep ocean, in and around hydrothermal vents, the underwater geysers that spout streams of hot and mineral-rich water out of the seabed. Although this water is anything but benign, a variety of highly specialised bacterial species can nonetheless cope with it. They form the lowest rung of a food chain that includes shrimps, molluscs, tube worms and much else. If all other life on the planet disappeared, these small ecosystems would continue to exist.

Back in the summer, a group of Japanese researchers led by Satoshi Nakagawa at the Japanese Agency for Marine-Earth Science and Technology described how they had analysed the genetic make-up of two species of vent bacteria and compared their genomes with those of a number of strains of Helicobacter and Campylobacter . This allowed them to construct a family tree from which it emerged that, long ago, today's ocean-dwelling and gut- living species must have evolved and diverged from a common deep-sea ancestor. This, according to Anna-Louise Reysenbach, a South African biologist now based at Portland State University, would have been a bacterium living under circumstances not unlike those found in today's hydrothermal vents.

The interior of our gut is neither as hot nor as chemically challenging an environment as an undersea vent. "But it's still pretty extreme in its own way," Reysenbach says. Her group's studies have demonstrated that the two groups of organisms share genes relevant to survival under both circumstances. They include genes for sensing the environment, for metabolic control and for coping with extreme conditions.

As Reysenbach points out, the uncertain life of a free-living microbe becomes less uncertain if it can associate itself with a larger creature. Colonising its surface is a first step; entering it would be a second. "Organisms that become parasitic or pathogenic are often opportunists. And what starts opportunistically becomes a habit." That said, precisely how the descendants of a microbe living in the deep ocean might have found their way into the human gut will remain a matter of speculation.

This link to the sea is a piece of evolutionary history; the link to the soil, by contrast, is a continuing and active one. Soil microbes live a fiercely combative existence and have long been known to produce all sorts of antibiotic molecules with which to attack competitors. Erythromycin and tetracycline are just two of the better-known products of the drug industry's success at screening soil samples in search of new drugs.

Where there is attack, there must also be defence. It wasn't the drug industry that inspired microbes to invent antibiotic resistance; bacteria in the soil and elsewhere achieved this feat long ago in response to natural competitors. What has come as a surprise to microbiologists is the sheer variety of their defences.

Last year Gerard Wright, professor of biochemistry and biomedical sciences, and colleagues at McMaster University in Ontario took soil from various locations, isolated bacteria of the genus Streptomyces , and grew colonies of 480 separate strains. When they dosed them with 21 antibiotics in regular use by doctors, they found that every strain was resistant to a set of at least six, and some were resistant to as many as 20. Wright was amazed by the findings. He had anticipated that there would be some evidence of resistance, he says, but not on this scale and not to the newest drugs as well as the oldest, the synthetic as well as the natural.

Only on reflection did he begin to feel that this level of resistance might have been expected. "These organisms are in a state of constant chemical warfare. There are fungi and nematodes and insects and other bacteria all making their own chemical soup to poison their neighbours. They've developed an arsenal not only of specific resistance genes but also a whole series of more general (cellular) pumps that will, for example, pump noxious materials out of them."

If soil microbes are indeed one of the powerhouses of bacterial innovation, how might any new resistance genes they devise reach microbes that can infect humans? With relative ease. Some bacteria are opportunistic: able to survive outside a human host, but happy to colonise us when the chance arises. And all are promiscuous: adept at swapping useful bits of DNA with other microbes, including those of different species. Scientists may have made genetic engineering more systematic, but they didn't invent it.

For medicine, and so for us humans, the implications of this bacterial ingenuity are discomforting. Their capacity for innovation makes it quite possible that some soil microbes are already resistant to antibiotics the drug industry hasn't yet invented. But this, says Wright, is a reality we just have to face. His work, he thinks, should encourage a little more respect for these lowly organisms.

He also hopes that it will change the way we use antibiotics. "The organisms themselves don't make just one chemical," he points out. "They make many that work in concert." We should imitate them; rather than using a single drug at any one time, we should be using them in combination. Indeed, this is increasingly how doctors and drug companies are thinking. Wright's findings offer them powerful reinforcement.

In short, while some of our problems with bacteria may originally have washed in from the sea, the answers to many of them now lie in the soil.

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