The worms have their turn
C. elegans is a scientist's dream - easy to grow, easy to feed, and able to produce 300 children. It's already 'won' a Nobel prize for medicine, and now it could help us understand our social lives. Laura Spinney reports
Wednesday 04 August 2004
When Sydney Brenner gave his Nobel lecture in December 2002, he doffed his cap to the fourth joint-winner of the prize for physiology or medicine that year. In addition to himself and his two colleagues, John Sulston and Robert Horvitz, Brenner said that the honour should also be shared with
Caenorhabditis elegans, without whom the others could not have made their groundbreaking discoveries.
When Sydney Brenner gave his Nobel lecture in December 2002, he doffed his cap to the fourth joint-winner of the prize for physiology or medicine that year. In addition to himself and his two colleagues, John Sulston and Robert Horvitz, Brenner said that the honour should also be shared with Caenorhabditis elegans, without whom the others could not have made their groundbreaking discoveries.
C. elegans is a barely visible nematode worm that, fully grown, reaches the magnificent length of 1mm. Possessing a fully functioning nervous system that consists of 302 nerve cells, it lives out its brief existence in compost heaps and river banks, sustaining itself on a diet of bacteria. But for Brenner, who in 1963 chose it as a model organism for studying how genes regulate development, the worm was the ultimate lab workhorse. "The animals live in a two-dimensional world feeding on E. coli on the surface of agar plates," he told his audience in Stockholm. "They are easy to grow in bulk, each animal producing about 300 progeny during a cycle."
C. elegans quickly became a star, worthy of comparison with the mouse and the fruit fly for services to science. Brenner's early work linking genetic analysis to cell division and organ development laid the foundations for Sulston and Horvitz to identify key genes controlling that development - genes that have their counterparts in man. Among other things, their work has led to a greater understanding of many human diseases.
But Brenner had still higher hopes for the worm. He wanted to study the roots of behaviour, and realised early on that any attempt to link genes and behaviour would require an intermediate step: understanding how the nervous system is built and works. Since the three scientists made their prizewinning discoveries, the field has made rapid advances in that direction, and the latest was published recently in Nature.
All animals, including humans, react quickly to changes in oxygen in their environment. The drive to reach the right oxygen concentration - 21 per cent of the ambient air for humans - is the strongest there is, says Cori Bargmann of the Howard Hughes Medical Institute and University of California, San Francisco. Oxygen, or the lack of it, has an impact on our behaviour and health in ways that we have barely begun to understand, although we can see it in extreme cases. She points to the insomnia and other unpleasant symptoms of altitude sickness that humans suffer when deprived of oxygen.
But the molecular mechanisms underlying the response to oxygen deprivation are not well understood. All we know about mammals is that regulation of their red-blood-cell count and other physiological responses to changing oxygen levels involve a protein called hypoxia-inducible transcription factor, which increases or decreases the expression of the genes controlling those responses. But there must be something else involved too, because these so-called transcription changes happen too slowly to explain our lightning reactions to either an excess or a lack of oxygen.
Jesse Gray, who works in Bargmann's lab, and David Karow of the University of Michigan, Ann Arbor, have now worked out the mechanism that allows C. elegans to sense oxygen, and have shown the dramatic impact it has on worm behaviour. They believe a similar mechanism could be at work in mammals, including humans. Their discovery happened by chance, since it started with an attempt by Michael Marletta, in whose lab at the University of California, Berkeley, Karow was working at the time, to solve a different puzzle.
Karow and Marletta were interested in guanylate cyclase, a human enzyme that binds to nitric oxide (NO) and is critical for regulating blood pressure. Guanylate cyclase belongs to the same family of proteins as haemoglobin, the oxygen carrier in human blood. Both contain an iron-containing molecule called a haem group that binds the gas molecule. But the haem unit in haemoglobin cannot distinguish between NO and oxygen. So Karow and Marletta wanted to know how it was able to do this in guanylate cyclase, because without that ability, NO regulation could not work.
They realised a clue might lie in the structure and function of guanylate cyclases in other species. But when they came to study the enzyme in C. elegans, their confusion only increased. The haem group looked different from those they were familiar with in mammals, but similar to those in anaerobic bacteria. Unlike anaerobic bacteria, C. elegans requires oxygen to live, so they wondered what possible function the guanylate cyclase could be performing in the worm.
To find out, they teamed up with Gray and Bargmann, who is an expert on the behaviour of C. elegans. She recruited an engineer, Hang Lu, to design a device for measuring the worms' responses to oxygen. Placed over an agar plate populated with bacteria and worms, the small chamber creates a gradient in oxygen concentration from zero to 21 per cent.
To their surprise, they found that the worms naturally gravitated to a concentration of around 6 per cent - much lower than the 21 per cent they are exposed to in the lab. But mutants that lacked a gene coding for one particular guanylate cyclase, GCY-35, responded differently. They showed no striking preference for a low oxygen concentration, and were more likely to stay at higher concentrations. If the worms' optimum concentration is 6 per cent, this may have exposed them to severe oxidative stress - "the same kind of damage you get from radiation fall-out", says Bargmann. The researchers concluded that GCY-35 was acting as a vital oxygen sensor for the animals.
But they actually made two discoveries for the price of one. Bargmann and others have been puzzled for years by a curious behaviour of C. elegans. When feeding on those notorious agar plates, they tend to move frenetically to the perimeter, where they feed in clumps, even burrow into the agar, before slowly dispersing.
She suggests that clumping or aggregation is a survival strategy when the worms find themselves in an environment that is too rich in oxygen. The lawn of bacteria is thickest on the agar plate where the oxygen concentration is highest, at the perimeter, but because both they and the worms that swarm to them are consuming oxygen rapidly, the very act of clumping creates a zone of tolerably low oxygen concentration. Once it is low enough, the worms spread out again. The researchers used Hang's device to artificially manipulate the oxygen concentration, and watched the worms clump on cue, when they were prevented from reaching their preferred low concentrations. By contrast, a change in oxygen concentration from 7 per cent to 21 per cent had little effect on the aggregation behaviour of guanylate-cyclase mutants - because, says Bargmann, their sensing of the shift was damaged.
Marletta says that multicellular life exploded on Earth when plants began "polluting" the atmosphere with oxygen. But there is no reason to assume - as those who have studied C. elegans in the lab have to date - that oxygen-breathing organisms prefer the 21 per cent oxygen content of air. Behavioural adaptations to oxidative stress certainly exist in other species too. "The search for it in other animals is under way," he says, "And we have an approach to looking for it in humans."
But it turns out that this group of researchers was by no means the first to demonstrate a link between social behaviour and oxygen sensing.
Since the Nature paper was accepted, Bargmann has stumbled on a paper published by a British zoologist named Harold Munro Fox in the Journal of General Physiology in 1921. He showed that a simple pond-dwelling organism called Bodo sulcatus also clumped together, and he suspected this behaviour might be related to the oxygen in its environment. But since he was working only a few years after the end of the First World War, he lacked any sophisticated technology for creating artificial oxygen gradients - such as Hang's magic box. Improvising ingeniously, he slipped a leaf under the glass cover through which he was studying his subjects, and shone a light on to it, causing it to photosynthesise and produce oxygen. As the concentration of the gas rose, he watched the creatures seek each other out, and form a defensive clump.
Gradually, other researchers who have taken their inspiration from Brenner and want to understand the fundamentals of social behaviour - the instinct to congregate, for instance, and the biological basis of recognising others like yourself - are becoming aware that they have to first eliminate the strongest drive of all, the need to breathe the right mix of gas. The humble worm, C. elegans, might just shed some light on the complex science of crowd behaviour.
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