In the beginning was the worm,and the worm was with Sydney Brenner, in a back room of the Laboratory of Molecular Biology in Cambridge; and Sydney looked upon the worm, and saw that it was good. Jim Watson was around too, and looked upon the worm, but Watson comprehended it not. "This is twenty years ahead of its time", he said.

For what Brenner planned was to use the worm to discover how genes made bodies and then behaviour. And this was in 1965, before anyone had found and analysed a single gene for anything.

C .Elegans is about the most unremarkable nematode known to man. There must be others, even less obvious, lurking undiscovered in the crannies of the world since nematodes are overwhelmingly the most numerous animals on earth. If a Martian biologist were to collect, at random, five million animals from the earth, sampling everything he could find, from apes and penguins through fish to the uncountable myriads of insects, almost all of them, four million,would be nematodes. The best estimates of the number of their species range between 100,000 and 10,000,000. The wild disparity of these estimates means that for every species we know about there may be a hundred that haven't been discovered yet, or there may be only ten. If Brenner had been interested in an organism that was economically valuable, he might have picked any of the numerous nematode parasites which cause humans suffering - either directly: about half the world's population are afflicted with parasitic nematodes, which can cause some extremely unpleasant diseases - or indirectly, because they parasitise almost everything that humans eat: not just sheep and cattle, but plants ranging from coffee to carrots. Victorian biologists catalogued nematode parasites of lions, vultures, and seal's kidneys, these last growing up to 40 inches long. There is a gruesome saying among worm researchers that if everything on earth were to disappear except the nematodes, the outline of all plants and animals would be left, filled out by their nematode parasites. Just how close this comes to literal truth emerges from the fact that there are three different species of nematode found living in the rectum of the American cockroach Periplaneta americana. There appears to be nowhere these animals will not try to live.

Yet elegans lives in tranquil obscurity underground, parasitising nothing, eating only bacteria and slime moulds.

The greed of C. elegans, though effective in the short term, causes it long-term problems, because the animals will devour all the food available to them as quickly as possible. Nor are they well-adapted to long foraging voyages. The answer to these problems is supplied by the dauer state, which corresponds to the strange encystments practised by many parasitic nematodes. As soon as a worm is hatched, the growing, feeding first stage larva is sensitive to two chemicals in particular which it samples or smells through the bumps around its mouth. One is a pheromone produced by all worms, with extremely long-lasting effects. This means that a growing worm can smell pretty accurately how many worms are sharing her patch of bacteria. The second chemical that larvae are sniffing around them is the smell of food. If the smell of worm is stronger than the smell of food this sends a signal that there won't be much to keep an adult alive. The growing larva can distinguish between different strains of bacteria, and modifies its choice according to the nutritional value of the available food. Just what constitutes "stronger" is affected by temperature, too. The higher the temperature around a worm - they thrive best at around 20° — the more likely it is to turn towards dauer.

Normally developing larvae spend only seven hours in the second stage of their lives, and most of this time is spent growing their gonads and eggs. But a worm that senses too many other worms around it, and too little food, will spend nearly twice as long as a second-stage larva, and in this time it will lay up fat in the cells of its skin and intestine rather than developing eggs. When next it moults, to become a level three larva, the dauer is immediately recognisable for the outside. It is thinner and darker than a normal worm. Their stomachs have closed up: in fact the mouth is completely closed by a block of the cuticle that normally forms the worm's outer skin, and the pharynx is shrunken. Their skin acquires a protective, water-repellent coating. In this stage, they can survive for up to three months, waiting for food to reappear. They are passive, but not inactive. Think of them as sulky adolescents, conserving their energy for some grand adventure which may never come. They will move quickly if touched, and they seek out water: when left in petri dishes in the lab, they crawl at night into the droplets of condensation that form inside the lids and there form huddles. But mostly they just lie around the agar, waiting for fate, or food.

Most of the life of a worm is spent eating, something at which it is fantastically efficient. Fifty per cent of the weight of bacteria it eats is converted to worm tissue, and its mechanisms for doing so are brutally efficient. The mouth cavity of elegans, seen under a scanning electron microscope, has six diamond-shaped bumps around it that compress the opening into something shaped like a star of David. There is a photograph showing this head, full of vast and formless menace at 8400x magnification, with a few hapless bacteria dangling from the lips. The sensory bumps or studs surrounding the mouth have tiny channels in them, which the nematode uses to smell the world around it, and to detect the chemicals release by other worms.

As an invertebrate, elegans has no jaws or teeth. Instead it has a pharynx, a short, muscular tube with a round bulb or crushing chamber at the far end. Each section of the pharynx lies between three muscles running along its length. At rest, these muscles relax, constricting the tube between them into three folds like a Mercedes emblem in cross-section. When they contract, the sides of the pharynx spring apart to make a triangular tube, into which any liquid in front of the worm is sucked. When the muscles relax again, the liquid is expelled but any food particles it contains are trapped within the pharynx. It's odd to reflect that this is essentially the same method of feeding used by the largest animals on the planet, blue whales, who also suck their food in as liquid and then strain out the good bits. Whales, however, have visible strainers for their food. The worm has no strainers visible, even in an electron microscope. The separation may be accomplished by some exquisitely tuned turbulence in the liquid as it's pumped through this channel much thinner than a human hair.

From the worm's pharynx, the filtered-out bacteria move backwards to the grinding bulb at the end, lined with knobbly projections which crush open the bacteria, so their nutrients pass backwards into the gut, propelled at high pressure by the pumping muscles of the pharynx. The interior of the worm is pressurised: if you prick one it does not bleed but it will burst. This means that it needs no muscles in the intestine. All it needs to do it relax the muscle closing off the other end and everything left from digestion is expelled at the anus: the healthy worm defecates about every 45 seconds all its life.

The most important thing about C. elegans at the beginning, apart from the fact that it could be displayed under an electron microscope in illuminating ways, was its sex life. It has sex early and often, usually with itself. These two facts make it fascinating for geneticists. C. elegans takes less than four days to grow from an egg to an egg-laying animal so the results of an experiment are quick to appear. The sex organs of a hermaphrodite C. elegans take up most of the middle of its body., they resemble an art nouveau "y" that has been squashed flat, so that the very short stalk is the vulva, and the two long arms, each folded back once on itself in a hairpin bend, are the gonads, where eggs and sperm develop. The eggs start to develop at the far point of the hairpin, and gradually grow as they move around the bend in the tube towards the vulva. The sperm, which are repulsive to look at , lurk at the exit of this tube, and fertilise the eggs before they move into the vulva. Unlike most animal sperm, those of nematodes have no tail and don't wiggle or swim; instead, they are amoeboid blobs, that drag themselves along a surface by expanding and contracting the cell walls like tiny caterpillar tracks.

Once fertilised, the embryo develops inside the eggs until it has grown to a tiny larva, which hatches once the eggs have been expelled form the vulva. Since the worm and its eggs are transparent, this process can actually be watched through a microscope as it happens

The mathematics of worm sex are simply mind boggling. I once tried to work out how many worms had laid down their lives for science in the last thirty years, and decided very rapidly that the number was incalculable. I mean that quite literally, and not just because my spreadsheet refused to contemplate them. The beginning of the calculation is quite easy to make: a worm will grow to maturity in about three and a half days. After that it will start laying eggs. Most will lay about 300 eggs in over the next four days; each of these will hatch in four days' time into a hermaphrodite that will lay another 300 eggs. So one worm has three hundred children and 90,000 grandchildren. These 90,000 worms would, if food were unlimited, produce 27 million children of their own. By the end of a month, assuming unlimited food and room, one worm could have eight thousand million living progeny, or, as an American would say, eight billion. There aren't that many people alive on earth. After the second month , each of those eight billion worms could have produced another eight billion descendants giving as the total number of possible descendants of one hermaphrodite in 69 days a figure that has 27 zeros after it. No wonder the spreadsheet boggled. When God promised Abraham descendants who would outnumber the stars in the sky or the grains of sand on a beach, he didn't mention that he had made the same promise to a worm first.

Brenner is not beautiful in repose. But the force and intelligence of his features are astonishing. Even as an old man, almost bald, with eyebrows that burst out like the roots of a small forest, he seems to fill a room with vigour. His eyes are a curious bluey-green - a colour I have only otherwise seen in trout streams in winter in the Slovenian Alps - when he starts to talk you are swept along in the icy buffetting current of ideas, shocked and exhilarated to the point of exhaustion - and still he goes on talking. Profundities, puns, anecdotes and opinions all rush and jumble together. "the only time I was able to talk science uninterruptedly with Sydney came when he was in hospital after a bad motorcycle smash" said one of his collaborators years later. Otherwise, he will talk about almost anything. "Was grandfather born stupid, or did he have to work at it" one grandchild asked his grandmother, bewildered by the rush of puns.
If Sydney Brenner in full flow reminds me of an alpine river, bounding along in an invigorating froth of brilliance, John Sulston has the self-sufficient buoyancy of a dry fly, able to ride the craziest rapids. This is not just because he is well hackled, with a badger beard and hair that - now trimmed down - used once to form a halo around his face. There is also an unsinkable sturdiness to his manner; a kind of enthusiastic competence that inspires trust.

He did not at first seem destined for any sort of leadership. He came from the kind of high-minded middle-class background that you would nowadays find preserved largely among Quakers. His father was an army chaplain (an Anglican) who became the secretary of a rather low-church missionary society. His mother was a teacher of English. Like John White, he was a fiddler and a tinkerer as a child: a passion for clockwork seems to distinguish molecular biologists. More than any of the people I talked to, Sulston is unashamed about his pleasure in toys, in mechanisms, and what he calls that "artisanal" side of a scientist's work. He was the first man to learn the trick of freezing worms so they could be thawed out alive. Actually, this works best with very small larvae, but in any case, it was an absolutely necessary technical breakthrough if the worm was to become a reference animal for biology. Without the frozen reference stocks going back to the 1970s the worm could have been quietly evolving in laboratories or accumulating all kinds of deleterious mutations; but if that seems to be happening now, it is simple to wash away all the suspect worms and thaw out a fresh batch of the original vintage. Equally, the ability to freeze mutants of interest means that these are always available as soon as anyone needs to investigate one.

Horvitz is disarmingly modest and mild and it takes an effort, listening to him tell the story of his life as if it had been an engaging shambles, to realise that here is a man who got two degrees at MIT in four years while editing the student newspaper, and then waltzed into a job in a lab run by two Nobel Prize winners before going on to get one himself.

Now he is a neatly trimmed man, drawling seriously in a spacious and comfortable office at MIT. But in the Seventies he had the hair, the sideburns, and the heavy-framed glasses of the serious radical. The whole lab was full of counterculture in the early years, like everywhere else.

One of the reasons he had gone into biology was that he felt that economics was too remote from the real world. He wanted to change big things. He wanted to understand the brain. He thought that with a degree in maths and one in computation he was most of the way there, but a rigorous training in biological research was exactly what he wanted. Rigour - and excitement - were what he got. The genetic code had only been fully worked out in 1966, and he started in graduate school in 1968. Molecular biology was growing in ways that made it hugely exciting, and almost incomprehensible to an outsider, even one as clever and energetic as Horvitz: "I can remember sitting in courses in my first semester and I had no idea what people were talking about. I can remember thinking 'If I don't have a better idea at the end of the year, I'm doing something else', because I didn't think I had a chance in this business."

But he struggled on. By the end of the year, he had not only begin to understand what his lecturers were saying, he had found it was fascinating. But the phage he was working on were further from having a nervous system, and had less behaviour, even than the bacteria they preyed on. If he wanted to approach the problem brain, he would have to work on an animal, and the choice was between the fruit fly and the worm. The fly was more respectable, in scientific terms. But the worm seemed to him far more interesting, for all the reasons that had appealed to Sydney Brenner. Horvitz, like Brenner, wanted to hack at a nervous system with genetics, and the tiny, prolific worm had to be better for that than the large and relatively slow-breeding fly. That seemed obvious to him, even though there had not been a single paper published on it then, despite six years of work. Applications for a post-doctoral post are meant to be garnished with references to the scientific literature that show the student is entering a fruitful and interesting research project. Horvitz had one reference on his, and that was a "personal communication", scientese for gossip.

He had never met Sydney Brenner, nor been to the English Cambridge, but the woman he was living with had toured England earlier, and assured him that it was a beautiful city. That did it. He wrote to Sydney, found a post, and the couple crossed the Atlantic to his new job. As they got off the train, his girlfriend looked around her and announced that she had never seen the place before. She'd been thinking of Oxford all the time. Despite this setback, Horvitz thrived.

To be a computer person in the late Sixties was to be a misfit almost by definition, but White was not even a very conventional computer scientist. He had grown up as one of those boys who is always building gadgetry: "bombs and rockets and radios, that sort of thing" he says, as if the logical connection were obvious. But when he left school he just dropped out for a while, until he found himself working as a technician at the MRC laboratories in Mill Hill, North London. He ended up in an electronic lab, making gadgets for the rest of the lab; and this awoke an interest in biology. He was obviously bright, so the MRC encouraged him to finish his education with with a sandwich degree, where he worked part time and took courses in six month bursts.

Once he had secured this degree, he reckoned he had better things to do in life than to make gadgets for other people. He was working on the ways in which nerve cells make connections and store memories, and at the same time beginning to dabble in computer graphics, but there didn't seem to be any research jobs available at the London MRC, so he applied for a job putting computers into telephone exchanges. Just as he was about to accept this, his boss in London told him that a man in Cambridge was interested in computer graphics, so he read up on DNA in Scientific American, put on his only suit, and went up for the interview, where he found Sydney Brenner chain-smoking in jeans and a Breton fisherman's shirt. "He didn't stop talking really. He talked to me all about these things he was going to do: cell biology, developmental biology, and how the nervous system works - all this sort of thing. It was really quite extraordinary. We shuffled around the labs and I was absolutely bombarded. As I left, he said, 'Well, you know, there'd be no trouble about you transferring because this is just another MRC appointment'."

Rothschild wanted to look at sea urchin sperm under an electron microscope, then very new and rare; at first they had to travel to the physics unit at the Cavendish labs to use one. So Nichol Thomson became one of the first men in England to master the crafts, perhaps the dark arts, of preparing specimens for the electron microscope, and soon one of the best at getting pictures out of it. One of the things that I came to understand about the worm project was that when scientists say they couldn't have done the work without their technicians, they are entirely honest and often sincere. One thinks of scientists as being distinguished by their precision of thought, but this is useless unless it is matched by precision of experiment.

By the late Sixties, Thomson was so good at preparing worms for the microscope that it became feasible to want to model it by making 20,000 slices through this creature which is only a millimetre long. The skill and dedication involved in such work was at least as great as that of anyone else in the project. Sydney, thought Nichol Thomson "a very talented lad" and was very keen to work with him; it's typical of the style of the MRC that when I asked Thomson whether anyone else in the world could have done his work, he replied "I don't know" in a tone suggesting the question was really difficult to answer.

Most of the work on the worm was done by people of exceptional energy and drive. None of them - except perhaps Brenner - had had careers that ascended in straight lines, if only because the worm, when it started, was off to the side of any imaginable career path; but all of the crucial early workers ended up at the summit of their professions. John White is at the University of Madison, Wisconsin; John Sulston ran a third of the public human genome project and Bob Waterston ran another third; Bob Horvitz is at MIT. Brenner, Horvitz, and Sulston shared the 2002 Nobel Prize. Eileen Southgate, however, lives in a small house outside Cambridge, as she has done for 16 years. She went to the lab as a technician, and retired as one. Yet her contribution to one of the great worm projects was as immense as anyone's. She did get credit for it, both in conversation and in history. This isn't a story of a woman overlooked by the scientific establishment. But it is very easy to overlook the role that is played in scientific advances by a disciplined lack of imagination and a simple willingness to trudge onwards, doing what amounts to high-class factory work.

Eileen Southgate had worked at the LMB since leaving school at sixteen in 1956 when she was offered the chance to help, as careers officer said, with medical research: "It was a choice of three jobs from school, actually. It was in the days when they came to the school with jobs and said, you know, you have a choice of three. One I couldn't get to, the other one I didn't really want and I chose this one. There was another girl there I'd been to school with, whom I knew, so …"

What did she like about it? "It was easygoing. It was then only, of course, a small group of about thirty people so it was very friendly, just like a family, really."

The Guardian

The New Scientist

The Daily Telegraph

The Sunday Times

a pretty pair of worms

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