IN A small dish in a lab at the University of Chicago, millions of bacteria are deliberating among themselves. For hours there is no activity then suddenly, having taken a vote and come to a decision, the bacteria all light up, filling their world with a soft blue glow. Nearby, other bacteria are navigating as a pack. In response to unseen signals, individual bacteria have grown tendrils and gathered together, forming a raft that glides easily over the solid surface.
Extraordinary behaviour for bugs? Biologist Jim Shapiro doesn’t think so. He watches this sort of thing every day in his lab. And he regards it as yet more evidence that the popular view of microbes is way off track. For most of the two centuries since scientists first peered into the microscopic world, they have viewed life’s tiniest members as loners, living individual, independent lives. But Shapiro and other biologists know that there is no such thing as an antisocial microbe. Bacteria, amoebas and yeast are not renowned for their social skills, but Shapiro thinks they should be.
Wherever microbes coexist in rich profusion – which is pretty much everywhere, from the scum on a pond to a cockroach’s gut – teamwork and cooperation count every bit as much as cut-throat competition. And behind it all stands a talent for communication that is turning out to be far more sophisticated than anyone imagined. Bacteria use a bewildering range of chemical messages not only to attract mates and distinguish friend from foe, but also to build armies, organise the division of labour and even commit mass suicide for the good of the community. Some experts even talk about “microbial language”, with its own lexicon and syntax. That is a radical interpretation, but microbes are certainly much cleverer than we thought. They are not just stupid little bags of enzymes, insists Shapiro, but “formidable and sophisticated actors on the stage of life”.
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The idea that microbial communities might be intensely social has been around for about 20 years, but most biologists did not take it too seriously. In the lab, researchers usually keep microbes as prisoners in well-stirred suspensions, which prevents them getting together to form colonies. That is fine for many types of research, but anyone interested in animal behaviour knows that the only way to get a real insight into what creatures do is to study them in their natural settings.
And away from the artificial simplicity of the lab, microorganisms adore surfaces. You’ll find them almost anywhere, from the hulls of boats and the walls of pipes and drains to the surfaces of ponds, water tanks and living organisms. “Of all the cells that make up the healthy human body,” points out biologist Jim Deacon of the University of Edinburgh, UK, “more than 99 per cent are microorganisms living on the skin, in the gut or elsewhere.” These surface-dwelling communities, often containing hundreds of distinct species, are known as biofilms. The microbes within a biofilm collectively weave a matrix of sugary polymers called exopolysaccharides that form the physical infrastructure of a slimy microbial city (żěè¶ĚĘÓƵ, 31 August, 1996, p 32). The community living within often has a strength and integrity its individual citizens lack.
Earlier this year, biologist Staffan Kjelleberg and colleagues at the University of New South Wales in Australia showed, for example, how forming a biofilm can enable bacteria to defend themselves against predators. The versatile bacterium Pseudomonas aeruginosa thrives in sewage-treatment plants and in the soil, but everywhere it falls prey to voracious protozoans. “On the surface of a pipe,” says Kjelleberg, “protozoa move just like vacuum cleaners.” He and his colleagues found that colonies of P. aeruginosa could develop into dense biofilms that were resistant to attack. “They form a structure that protozoa find hard to eat,” says Kjelleberg. In comparison, colonies of mutant bacteria deficient in the art of biofilm development remained easy prey.
The biofilms in these experiments are extremely rudimentary. Natural biofilms – in everything from dental plaque to spoilt food – are so complex that researchers still cannot reproduce their full glory in the lab. Yet by studying microbes in somewhat simplified settings, they are peeking into their social lives and learning how they get it together.
Group action
One of the most important techniques microbes use to coordinate teamwork is known as quorum sensing. In the laboratory of Bonnie Bassler at Princeton University, a bacterium called Vibrio harveyi shows how it works. These bacteria routinely produce a molecule known as an autoinducer, which they release into the environment. The result under many conditions is precisely nothing. But at a high enough concentration, the autoinducer triggers a chemical response in other V. harveyi, making them glow. The concentration of autoinducer reflects the density of the bacterial population so, when numbers are high enough, the bacteria will spontaneously light up with a dull blue luminescence.
So, while V. harveyi will not shine as an individual, it does in a group. Biologists are not yet sure what it gains by this behaviour, but many other bacteria perform similar feats, and in some cases researchers have found out why. Outside the lab, the marine bacterium V. fischeri – a close relative of V. harveyi – often lives in dense colonies on the Hawaiian bobtail squid. The squid gives the bacteria a protected environment in which to multiply and, in return, the bacteria light up, helping to camouflage the squid in its deep-sea habitat. When swimming alone in the sea, the bacteria don’t bother to glow – they save their energy.
Biologists discovered the basic logic of quorum sensing in V. fischeri in the 1980s. Over the past decade, Bassler and others have learned that most microbes exploit similar tricks. In the lungs of cystic fibrosis patients, for example, P. aeruginosa uses quorum sensing to decide when to deploy virulence factors – molecules that ease its entry into tissues or help it to counter host defences. By relying on a system that is only triggered into action when a crucial threshold is reached, the colony avoids stirring up the immune system too early. Instead it assembles a formidable force before launching the invasion proper.
When threatened with starvation, the soil-dwelling bacterium Myxococcus xanthus responds with a similarly impressive display of social coordination. When the concentration of autoinducer reaches a critical level, many individuals commit what appears to be socially inspired suicide. The cells disintegrate, releasing raw materials that ensure the survival of a lucky few. These become quiescent spores wrapped within a fruiting body formed of less lucky cells, which gives them a good chance of surviving to germinate when conditions improve.
Hundreds of microbes use quorum sensing, but experiments with V. harveyi in particular have revealed the potential flexibility of this communication strategy. Two years ago, Bassler and colleagues discovered that V. harveyi has not just one quorum-sensing circuit but two, and uses them in combination, like tools in a carpenter’s workshop, to orchestrate more subtle acts of cooperation.
One of the circuits in V. harveyi triggers light production only when it senses a quorum of bacteria of the same species. But the second circuit, operating through a distinct set of autoinducer molecules, is not so picky. It triggers light production when enough bacteria of any species happen to be nearby. “It seems paradoxical,” says Bassler, “that these bacteria use two systems when either alone should be sufficient.” But she suggests that having two systems might allow V. harveyi to modify their behaviour in subtle ways, depending on whether they are in the minority or the majority in a community of species.
“Microbial signals are like a real language in that they represent words whose meaning can differ in different contexts”
The discovery of quorum sensing and its widespread use in the microbial world has ushered in a new view of microbes as highly social creatures. Indeed, the level of cooperation between individuals can be so complex that they act less like a coordinated group of single-celled organisms and more like a microbial “superorganism”. Just as multicellular organisms depend on cellular differentiation to create specialised cells to make muscles and nerves, for example, microbial colonies do the same. “You look at these biofilms and you find a lot of differentiation,” says Kjelleberg. “They really are like higher organisms.”
Shapiro points out that even simple colonies of the same species can be highly sophisticated, as cells in distinct regions differentiate to produce what amounts to different tissues. The bacterium Proteus mirabilis swims easily in a liquid using its few whip-like flagella, but individuals cannot move over a solid surface. A colony growing on a surface can, through chemical communication, orchestrate a collective metamorphosis in which many of the bacteria turn themselves into elongated cells covered with thousands of flagella, which they can use to move over the surface. “These cells are sensitive to touch,” says Shapiro, “and they like to line up next to one another.” The resulting raft of specialised bacteria helps the colony to spread by swarming over surfaces on which ordinary individuals would remain stuck. The swarming bacteria can later return to the normal condition, which is more suited to swimming.
Given that quorum sensing allows microbes to talk to one another in order to cooperate, it is not surprising that some organisms have learned how to disrupt their enemies’ communication systems. As a saboteur, the bacterium Bacillus subtilis produces a molecule that modifies the autoinducers used by many other bacteria, thereby ruining their effectiveness. And the marine red alga Delisea pulchra, common on the coast of southern Australia, produces chemicals called furanones. Similar to autoinducers, these molecules effectively swamp the receptors of microbes’ quorum-sensing systems, jamming communication. “The algae paint their surfaces with these molecules,” says Kjelleberg, and so defeat microbial attack.
This particular countermeasure turns out to be popular among microbes. “We have a whole freezer full of organisms that do similar things,” says Kjelleberg. “There are really a lot of them.” Stimulated by this discovery, he and his colleagues have produced synthetic molecules that they are trying to develop into new antibacterial drugs. Unlike conventional antibiotics, these would function not by killing the individual microbes, but by destroying their ability to communicate and cooperate.
It’s not just outsiders that are bent on subverting the teamwork of social microbes. Sometimes the sabotage comes from within. In any society where you have individuals cooperating for the good of the group, you are likely to get freeloaders who refuse to pull their weight but still enjoy the benefits of being part of a collective. Microbial societies are no exception. Last year, biologists Gregory Velicer and Francesca Fiegna of the Max Planck Institute for Biological Cybernetics in Tübingen, Germany, witnessed the consequences of cheating in a colony of M. xanthus, which would ordinarily form a “fruiting body” in response to a crisis. Normally, it seems to be a lottery as to which individuals sacrifice themselves and which benefit from the collective response by becoming spores and passing on their genes to the next generation. But when Velicer and Fiegna augmented the colony with a few mutant individuals from populations that could not form fruiting bodies, they found that these mutants contributed less than the normal bacteria to fruiting-body formation, and were more likely to become spores.
As well as giving a fascinating insight into the biology of cheating, the study also throws light on one of the classic puzzles of evolutionary biology – why cooperation between individuals persists despite the potential threat from freeloaders. Velicer found that the mutant bacteria contain the seeds of their own destruction. Because they greedily push their own genes into the next generation, the freeloaders proliferated rapidly in the community, displacing cooperators. This outbreak of cheating eventually led to a dramatic population crash, and in some cases the colony perished entirely. This isn’t an ideal outcome for anyone, and it is likely that microbes have evolved ways to police cheating and preserve cooperation.
How cheaters could be stymied remains a mystery. Velicer points out that a society of microbes might direct extra benefits to those who don’t cheat, or might directly punish cheaters. This would probably entail forms of communication that are so far unknown. But he is hopeful of finding them, given the great progress in uncovering the vast and complex world of microbial communication. Velicer is certainly not alone in his belief that there is much more to be discovered about microbial communication. “We fully expect that this is merely the tip of the iceberg,” says physicist Eshel Ben-Jacob of Tel Aviv University in Israel.
What’s more, if Ben-Jacob is correct, microbial communication is more than just an intricate exchange of chemical messages. He believes it is something akin to language. In a recent article, he and his colleagues argue that when other researchers talk about the “syntax” of microbial signals, or their “contextual” meaning, they should consider the possibility that this is more than a metaphor (Trends in Microbiology, 2004, vol 12, p 366).
Words and meanings
Microbial signals are like a real language, they argue, in that they represent “words” whose meaning can differ in different contexts. As with human language, bacteria possess a lexicon, or vocabulary, of possible signals with which to communicate the various signaling chemicals they produce and recognise, such as those used in quorum sensing. And the meaning conveyed through these signals depends strongly on the semantic context. Bacteria carry internal information reflecting their history as well as current external conditions, and can respond to the same signal in different ways at different times, showing a rich behavioural repertoire.
Ben-Jacob’s interest in microbes indicates a changing attitude towards Earth’s smallest inhabitants. At last people are waking up to the fact that most of life is microscopic, and that the macroscopic bits wouldn’t be what they are without microbes. The discovery that these two worlds have much more in common than we thought is intriguing. More and more researchers agree with Ben-Jacob’s assertion that microbes have the kind of social intelligence previously considered to be the exclusive preserve of the most intelligent animals. Microorganisms recognise the social groups to which they belong, and readily pick out strangers who might pose a threat.
As we find out more, we will perhaps perceive microbes as more like ourselves, or discover the roots of our own social behaviour in the supposedly “simple” microbial world. Perhaps our own ability to talk and communicate, to form teams and root out and punish freeloaders, goes all the way back to our days as bacteria.
