The 1950s and early 1960s had seen a dazzling explosion in molecular biology. The structure of DNA had been solved, the flow of information from DNA to RNA to proteins - the central dogma - had been worked out, and the mysteries of biology seemed eminently solvable. As Francis Crick would say: "Suddenly you're asking the right questions."

If the 'classical' problems of molecular biology had or would soon be solved, what was to be 'the next big thing'? For the young South African scientist Sydney Brenner, who had worked with Francis Crick on the deciphering of the triplet code, the task was clear. As he wrote to Max Perutz (then head of the Laboratory of Molecular Biology in Cambridge) in June 1963: "The future of molecular biology lies in the extension of research to other fields of biology, notably development and the nervous system."

By applying the genetics techniques that had been so successful in unravelling the secrets of molecular biology in bacteria, Brenner proposed to tackle the role of genes in more complex processes in a multicellular organism. But what organism? Other researchers, thinking along the same lines, plumped for old favourites such as the fruit fly. Brenner's choice, as set out in a proposal to the Medical Research Council in October 1963, was a surprise. For the nematode worm was an unknown in the world of model organisms. The original proposal was for the study of the nematode Caenorhabditis briggsae; sometime later, its cousin, C. elegans, was chosen in preference.

Forty years later, and the wisdom of this choice has been vindicated not only by the impact of the worm on fields as diverse as development, behaviour, ageing and genomics, but also by the award of the 2002 Nobel Prize for Physiology or Medicine to three worm biologists: Sydney Brenner, Sir John Sulston and Bob Horvitz.

"For Sydney Brenner, the Nobel Prize is a great and well-deserved accolade," says Dr Sulston. "When he picked this organism in 1963, it was a gamble: no one knew then whether it would deliver in real terms, and the worm has delivered in all sorts of ways."

Why the worm?

Sydney Brenner was looking for an organism that had simple and rapid genetics, that would grow quickly and could be kept in the lab conveniently, and was small - so that its anatomy and ultrastructure could be examined easily. It was a very systematic selection, and the worm fitted these criteria very neatly (see box below).

Although the worm is much simpler than humans - it doesn't have bone, a heart or a circulatory system, for example - many of the signals involved in development are also found in more complex organisms. "It's very important that when you're choosing a model organism, it must not only be convenient to work on, but it also has to be related to other things that are useful," says Dr Sulston.

With the goal of making the link between genes and behaviour, Sydney Brenner started making mutants, on a scale that had not been tried before. "The genes have to specify the cells, which have to build themselves into a nervous system, muscles and so on," says Dr Sulston. "The mutants are a way into finding these genes."

The most exciting mutants - for Brenner - were those that affected behaviour. For example, he found some worms that could not go backwards. There is a rational explanation: in some of these mutants, particular subsets of nerve cells are absent.

The birth and death of the cell

As the research in Cambridge expanded in the late 1960s and 1970s, there were a number of projects going on in parallel, studies of cell lineage, genetics and electron microscopy coming together and explaining each other. "It was a burgeoning group of people driven by the excitement of new territory," says Dr Sulston. "This beautiful little animal did not have the weight of history behind it like the fruit fly: it was as though we were exploring it for the first time."

John Sulston joined the group in 1969 and spent the next decade working out how the worm develops from a single cell to an adult. Under a light microscope, the fine detail of the cells inside the worm can be seen, the division of the cells followed as it develops. "Once I saw this, I was totally entranced," says Dr Sulston. "For a long time, I didn't want to do anything other than watch the cells developing."

Each worm is made up of about 1000 somatic cells (about a third of which are nerve cells), and a similar number of germ cells in the gonad. The mapping of the path from a single cell to the 1000 cells of the adult - a task that took a decade to complete - showed, remarkably, that the lineage is the same in the development of every worm. Not only that, but it uncovered an entirely new phenomenon - some of the cells never make it into the adult, being programmed to die during development.

The award of the Nobel Prize for the discovery of programmed cell death indicates its importance - for its implications go much wider than worm development. Cell death has a fundamental role in human development (removing the cells between the fingers, for example) and human disease. In AIDS, neurodegenerative diseases, stroke and heart attacks, cells are lost through excessive cell death; in other diseases, such as autoimmune conditions and cancer, cells survive that are normally destined to die.

Maps and genomes

By the early 1980s, the worm research community had generated a lot of mutants, but it was becoming clear that there was a bottleneck: finding the genes themselves. In the worm's genome of 100 million bases of DNA are scattered, as it turns out, 19 000 genes but at the time it was proving hugely laborious to isolate DNA and locate these genes.

"What it needed was a small group to go and map out the genome," says Dr Sulston. "And not just to make a map, but to make the links between the map and the genes." Dr Sulston and colleagues Alan Coulson and Bob Waterston (the latter at Washington University, St Louis) therefore produced a map of the entire C. elegans genome - multiple overlapping fragments of DNA, arranged in the correct order.

This public resource made finding genes much easier: once a researcher had found a mutant and worked out which area of the genome the gene might be in, the map group would send the DNA clones that covered that region. "Although there was some scepticism at first, it suddenly took off and the bottleneck had been broken," says Dr Sulston. "This was the beginning of genomics."

The worm was to have an even greater impact on genomics when it was chosen to be the first multicellular organism to have its genome sequenced. "We wanted to get at all the genes, and classical genetics - find a mutant, then find the gene - might not have been enough," says Dr Sulston. "But if you have the genome sequence, you get all the genes."

Half of the worm genome was sequenced in the UK by John Sulston and colleagues, funded by the Medical Research Council, and half in the US by Bob Waterston, funded by the National Institutes of Health. The sequencing was spurred on by Jim Watson, then head of the Human Genome Project, who was interested in having a pilot programme for the human work: "Jim Watson was crucial in both promoting model organisms as pilots and giving the worm some of the money to do it," says Dr Sulston.

The worm sequencing project began in 1990 and, working with the new automated DNA sequencing machines, met its target of sequencing three million bases in three years. This was an important proof-of-principle for the Human Genome Project, as it showed that the technology was scalable: with more money, more people and more machines, the three billion bases of DNA in the human genome could be tackled without fear.

The post-genomic worm

In 1998, the sequence of the C. elegans genome was published. The knowledge of the worm's 19 000 genes has already had a marked impact on worm research. The full genome has allowed whole gene families to be identified, reverse genetics (going from gene to mutation) to be undertaken, RNA interference to be used to systematically knock out each gene in turn, and the patterns of expression of genes to be examined.

"Genome sequencing is tool creation," says Dr Sulston. "You do it to provide a foundation for biology, to inform biology, and to provide tools that people can use. It shows the advantages of free access to the data: it speeds up research by years, and allows you to do things that could not be done before."

"It's been huge fun," says Dr Sulston looking back over the last 30 years. "Research on the worm has gone from mutants and cell lineage work, through to studies of the whole genome and research that is directly relevant to human disease. It's classic model organism work, and it has happened over a relatively short period of time."

See also

• Why the frog?
• Why fish?
• Why the fly?

External links

• Caenorhabditis elegans sequencing project: Further details from the Wellcome Trust Sanger Institute
• Further details on model organisms including C. elegans
• 2002 Nobel Prize for Physiology or Medicine: Further details of the award to Sydney Brenner, Sir John Sulston and Bob Horvitz