Triumph as scientists find what makes worm turn

They brought a worm to book. They completed and published the blueprint for an entire complex, multicellular organism. It may be small and it may be a worm but its basic functions are our basic functions.

Biology has lurched forward: the complete mapping of human genetic make-up gets ever closer.

It took 15 years in all, and involved identifying more than 97 million bits of DNA that add up to a recipe for more than 19,000 genes. These 19,000 genes are what it takes to make a worm turn. In fact, the genes make the worm learn, turn, squirm, eat, digest, and make what passes for love in the microscopic world of the nematode Caenorhabditis elegans.

This worm is no more than 1mm from end to end. It is about as simple as a multicellular creature can get, and it takes about four days to get from egg to worm. It comes in just two sexes: male and self-fertilising hermaphrodite, but it can still manage to produce around 100 offspring before it dies.

It now joins some other important organisms whose DNA code is now complete, and published on the Internet, for the benefit of researchers everywhere.

One of them is yeast, which has been providing cakes and ale for humankind for at least 6,000 years. Another is Helicobacter pylori, which has been providing modern humans with stomach ulcers for decades. A third is Treponema pallidum, better known as venereal syphilis, which has been a global health problem since about the time Columbus came back from America. Another is a strange little monster called Methanococcus jannaschii which lives in volcanic vents almost two miles under the ocean.

But these are all single-celled organisms: each one a microscopic blob of life's machinery. C. elegans is different: it is made of 959 co-operating blobs of living tissue.

The nematode may be too small even to step on, but it is a giant leap for mankind all the same. The research matters for its own sake - four out of every five creatures on the planet is a nematode worm - and as a measure of the sheer effort taken so far.

But there is bigger game to be stalked and bagged within the blueprint for a worm. The worm may be small, but it is the nearest organism to humans so far described.

It is a milestone in the race to map the DNA sequences of mice, rats, rice, thalecress, zebrafish, chicken, pig and other useful complex creatures. And it is a kind of short cut to the greatest prize of all: the entire three billion-letter alphabet that will spell out the 80,000 genes or so that describe what it is to be human.

That last should, if all goes well, be finished by 2003: a momentous date, exactly 50 years after James Watson and Francis Crick determined the structure of the double helix that supports the DNA code, the four-letter chemical alphabet that describes all life on the planet.

Crick and Watson are still working as scientists. That is a measure of the speed of the operation.

The scale of the achievement is already enough to make even the achiever reel: new human genes are being identified, described, examined and even tinkered with almost every week. The sum of a creature's genes is called its genome. More than 40 nations have joined the Human Genome Organisation to complete the project, at a cost - a figure plucked from the air, because nobody knows how to do the accounting - of about $3 billion.

The worm was turned to good account chiefly by a team from Washington University in St Louis and the Sanger Centre in Cambridge. C. elegans exists almost everywhere in the temperate world but the project started in Cambridge more than 30 years ago with some worms collected from decaying mushrooms in Bristol, although the systematic decision to sequence the entire genome was taken only in the 1980s.

Since then, Sanger scientists helped map the chromosomes of yeast; they are also working on fruitflies and pufferfish, chickens, tuberculosis, malaria and the little bacterium that delivers bubonic plague.

Yesterday morning, in the American journal Science, the Sanger Centre's chief, John Sulston and his colleagues, announced the completion of the worm project. As they see it, it's both an end and a beginning.

"We have in coded form essentially all the information needed to make an animal," Dr Sulston says.

"In a chicken-and-egg kind of way everything that is needed is written in the genome of C. elegans, which is the first animal to get sequenced. So there we have it. We can't understand it all.

"But if you want to understand how an animal works, what better basis can you imagine than actually having in your hand all the information, even if it is written in a code we cannot fully understand?"

He sees the 97 million-letter alphabet as a magnificent toolkit for understanding: a starting point for identifying all the genes in the little worm.

Genes make proteins. Proteins make tissue, and tissues make systems, and systems make behaviour. With the genetic blueprint, it is possible to see a little worm as a kind of complex, subtle, orchestra of parts which play together in almost magical harmony.

But mice, chickens and humans march to the same harmonies: research into the genomes of yeasts, bacteria, worms and humans tells the same over and over again: all life on Earth is intimately related.

If you can discover what makes a yeast or a worm tick, you have at least part of the answer to a human mystery. So each gene identified and catalogued is a prize for science.

The yeast scientists - a Europewide consortium - have had a couple of years' start. They already have a measure of the massive task ahead.

"In all of these organisms we find we do not know on any level what between 40 and 60 per cent of the genes do. Sometimes we recognise them, sometimes we don't. Even if you recognise them because they are similar to genes in other organisms, it doesn't necessarily tell you what their role in the organisms is," says Prof Stephen Oliver, of the University of Manchester Institute of Science and Technology.

But even yeast has genes that parallel human afflictions. One yeast gene produces a protein doctors recognise: it is called frataxin. In humans, it is produced by a gene that is linked with Friedrich's ataxia, a neurodegenerative condition which makes the legs unsteady. "Well, yeast doesn't have legs," says Prof Oliver. But yeast, being simple, can show exactly what the gene does: you can swap yeast and human genes and watch the effect at work in a laboratory dish. The worm will add to that value.

The next trick is to see what they do, how they work, and the instructions that set the genetic machinery in operation will also be coded in the DNA sequence.

The worm will be a kind of data resource for biologists for decades to come. It is beginning to answer questions about the machinery of programmed cell death, and therefore about cancer. It is beginning to answer questions about why cells grow old and die.

"The picture one has to have is that all sorts of things drop out immediately," says Dr Sulston.

"Most of the sequence has been out for years now and has provided lots of starting points for researchers. There are lots of new research projects starting up: it has stimulated a whole field of biology. There will be far more value yet to be extracted from it than we can see at this point."

The next enticement is gene therapy: treatment, based on precise knowledge, to repair the faults provided by heedless nature. The human genome project actually began with the search for individual genes that have blighted certain families for generations: muscular dystrophy, Huntington's chorea and so on.

The genes have been found. Treatment based on the knowledge of the genes so far has proved tantalising. Biologists can see what goes wrong in cases of, say, cystic fibrosis. But help for the sufferers is still a long way away.

"There will be lots of little individual breakthroughs which will benefit individual patients. There will be an ongoing series of advances which will depend, in part, on the genome. But they will also depend, of course, on experimental ingenuity."

That's the toolkit bit: the genome helps, but it does not provide instant solutions. But the knowledge is expected to pay off, handsomely, in terms of public health.

The betting is that people who die relatively early in life of heart failure, or stroke, or cancer, die because of their own peculiar mix of genes: evolution has a way of keeping people alive until they are ready to procreate and rear their young. Then, so to speak, it loses interest.

But genes are only half the story: the environment in which the genes survive or fail is the other half. The knowledge of the human blueprint is already beginning to provide useful information about the lifestyles and diets that tend to healthy maturity.

It is also beginning to present insurance companies and health authorities with some ethical headaches: if someone has "bad" genes, why would you want to accept them as a risk? If they have terrific genes, why should they pay your premiums? Right now, it is the worm's turn in the limelight. It was small, bred fast and it was transparent: researchers could actually see what was going on in the worm.

"It's simpler than a human, in terms of the range of organ structures, but it has a gut, it has muscle, it has skin and it has a got a nervous system," Dr Sulston says.

"It's a wonderful test tube for biology, you can move things in there, and have them work, and look at them more closely. We haven't come to the end of something. We have come to the beginning of something."

Further information from: the Human Genome Project website http://www.ornl.gov/TechResources/HumanGenome/home.html