The worm is perhaps the most abused creature in the history of the world
Itís a good job that c.elegans can feel no pain, because it is the most intensively studied animal in history, which means that untold millions of these tiny worms have been sliced up, irradiated, centrifuged at 100,000g (they survived), frozen, poisoned in interesting ways, fed alcohol, prozac, and even anaesthetic; in one celebrated episode, a researcher on a bet spread a hamburger bun with them and ate it. He survived, too.
Outside laboratories elegans spends its natural life in soil or dungheaps, eating bacteria. Little more is known of its life in the wild and no teams of researchers are competing to study it there. In the laboratory, though, things are very different. Since 1965, it has been the focus of an ever growing research effort which last month saw 1600 very smart people gathered on the campus of UCLA in Los Angeles to discuss everything that is known about the animal. These are the people for whom the tiny, transparent worm has become the lens through which they can study the whole of biology: Elegans is only about a millimetre long, transparent, and made of 959 cells. A human, by contrast, has about 50 billion times as many cells as that. We are also much less tractable experimental subjects and take far too long to breed. A worm is fully gorwn in three days, and seldom lives longer than three weeks.
It is paradoxically a great advantage that the worm is "about as boring as an animal can possibly be" in the words of one of Britainís most distinguished scientists (who does not work on it). The whole point is that the worm is just big enough to contain the great mysteries of modern biology but small enough to be almost completely manageable. It can be grown on glass dishes and fed bacteria, but it has sex, it has a nervous system and a gut, if not a brain. Perhaps the most complicated thing of all, which we tend to take entirely for granted, is the fact that it grows through different stages from one egg to a complete animal made up of many different sorts of cell, each in the right place. How does the fertilised egg know how to do this? It has behaviour, of a sort: one of the most surreal sights at the worm conference was to see the grandest auditorium of the university used to show huge films of worms mating. But this behaviour is simple enough that it can be disrupted in instructive ways by the failure of a singe gene: the worm blue movie was shown to illustrate what happens when the maleís nervous system loses the ability to respond correctly.
When you read that scientists have discovered ageing genes or the elixir of youth in "a worm", Elegans is the worm they mean. It was the first animal to have its genome sequenced ó the sequence was completed in 1998; and without the worm, no one would have thought it possible to complete the human genome sequence. Sir John Sulston, who ran the British end of the Human Genome project, started his scientific career on the worm, and made his reputation by the almost incredible labour of working out the exact sequence of cell divisions, deaths and migrations by which the single fertilised egg cell transforms itself into the 959 different cells of a complete worm. It may not sound very much, but even an animal as simple as the worm is horrendously complicated when sliced up beneath an electron microscope. The hermaphrodite worm has only 302 nerve cells (the very rare males have more): yet to establish exactly where every nerve runs and how it is connected to every other took fourteen years.
But mapping the growth of the worm, plotting the courses of its nervous system, and finally sequencing all of its DNA are only steps along the way to complete understanding. If the worm served as a spur to the completion of the human genome project, last monthís meeting in Los Angeles was a reminder how far there still is to go once the genome has been sequenced. For a start, there are the arguments about how many genes are actually contained in the genome sequence. There are still disputes about this in the human case: when the sequencing was completed, figures of between 30,000 and 120,000 were guessed at. The present best opinion is only about 30,000 genes, but last week researchers claimed they would find 60,000 when all were counted. Curiously, Sydney Brenner, the brilliant South African who started the worm project in 1965, also believes that the number of human genes will be much larger than is at present supposed.
The worm is believed to have about 19,000 genes but most of them are not properly understood. At the same time, there are uses for the "junk" DNA, which contains sequences that seem to do nothing at all except keep apart the genes. Some stretches at least are now known to have a function in the cell even though they do not code for a protein as "non-junk" DNA does. Even when a worm shares a gene with a human, the effects and uses of the protein that the gene makes may seem entirely different: one gene important in the wormís mating behaviour, in that males canít figure out what to do without it, can also be defective in humans; but in us ir causes a rare kidney disease.
"Itís difficult sometimes, when youíre dealing with all these sequences, to remember if youíre inside a human or a mouse" one of the researchers told the worm meeting. No one laughed. Down in the enormous databases that hold the endless strings of which make up everythingís genes, the whole world does look more or less the same. And it was the great triumph of twentieth century biology to discover and understand the essential genetic unity of life. But the next half of the program to discover and understand how all these similar strings of DNA gave rise to the extraordinary diversity of the living world around us. The worm was the first animal to be reduced to DNA, and it may be the first to be reconstructed, if only in a computer. But it turns out that you canít do that by studying the worm alone.
Despite these difficulties, worm science is thriving as never before. Though there are some companies hoping to make money from the worm, the subject is far less hyped than the human genome was; people study the worm because they believe it is a key to the whole of biology. Once you understand why the same gene can cause bizarre sexual dysfunction in a worm but kidney dysfunction in a human you will understand an enormous amount about the workings of both worms and human beings. That is the logic, too, behind feeding worms anaesthetic or even prozac. A worm has no consciousness to lose, yet it reacts visibly to drugs that cause humans to lose consciousness. Understanding what is going on in the worm then gives at least an opening into understanding the more complex internals of a human being or even a mouse.
Elegans is a nematode, a class of worms which contains parasites of almost anything that can have a parasite. 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. About half the human population of the world ó three billion people ó are infested with one of the relatives of elegans. Nematodes cause innumerable diseases of animals and humans, among them hookworm, roundworm, and elephantiasis in man; they also eat nearly everything that humans do, from coffee to carrots. Yet though these considerations explain some of the reasons for funding worm research, they donít explain why the researchers do it. Only a love of gaining knowledge, and an extraordinary ambition, can account for that. There is also a sense of fun about the project which is entirely unexpected, exemplified in the Internet trade magazine, the Worm Breedersí Gazette.
The final end of the worm project is to understand every aspect of the animalís biology so well that it can be completely simulated on a computer. This would reduce the whole life of the animal to a succession of well-understood mechanical, electrical and chemical reactions whose relationship with each other was entirely understood, and then rebuild its behaviour and patterns of growth from this understanding. This means that the final worm model wouldnít just imitate the animalís behaviour, it would let you predict the future behaviour from the inside, so to say.
There is still some way to get there. Professor Jonathan Hodgkin of Oxford University, who has studied the worm for decades ended the Los Angeles meeting with a talk about a bacterial parasite that constipates the worm so badly that afflicted animals were thought at first to be suffering from a mutation. It turns out that there are at least eighteen different genes which may mutate to give worms resistance to this bacterium. Fourteen of them hadnít been found before. "The function of a large fraction of the genome is totally unknown and I suggest that this will remain so until we know more about the life of the worm in the wild."
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