Confocal image of C. elegans

Human Genome Project history 3: The worm leads the way

28/2/01. By Georgina Ferry

The science that would provide the basis for mapping and sequencing the human genome was developed on a smaller scale: the sequencing of the genome of the humble nematode worm.

In the late 1980s and early 1990s, national funding bodies in Europe seemed less confident about spending the very substantial sums involved in genome sequencing projects. Many scientists were concerned that giving such a big slice of the biomedical funding cake to a single project would stifle creativity and narrow the range of science that could be supported.

Nevertheless, the science that would provide the basis for mapping and sequencing the human genome was already flourishing on a smaller scale. The technology that was needed to move from mapping, locating the positions of known landmarks throughout the chromosomes, to sequencing, spelling out one by one the sequence of bases along each chromosome, already existed.

Fred Sanger at the LMB in Cambridge had won his second Nobel prize in 1980 for developing the method of sequencing DNA that is still, with minor modifications, in use today. Sanger and his colleagues had also pioneered whole-genome sequencing - working with phage, tiny viruses that infect bacteria and have genomes only a few thousand bases long.

Sydney Brenner's laboratory was trying to come up with a full description of an organism, from genes to behaviour, by working with another simple species - the 1 mm long nematode worm Caenorhabditis elegans. By 1989, his colleague John Sulston, with Alan Coulson and later with Bob Waterston at Washington University in St Louis, had successfully produced a map of the entire C. elegans genome. The map consisted of multiple overlapping fragments of DNA, arranged in the correct order. Each identified fragment had been cloned in bacteria, providing the raw material necessary for a sequencing project.

James Watson believed strongly that the Human Genome Project should also encompass the genomes of smaller organisms that would both help to establish the technology and provide valuable sources of comparison once the human project was truly under way. As soon as he saw the worm map, Watson agreed that C. elegans should be the first multicellular organism to have its complete genome sequenced. NIH funded Dr Waterston's lab to begin a pilot project and also, exceptionally, put £500 000 into Dr Sulston's Cambridge lab to supplement funding from the MRC.

In 1990 when the worm sequencing project began, the first automatic sequencing machines were just becoming available. These machines, made by Applied Biosystems Inc., operated on the principle established by Sanger but used different coloured fluorescent labels instead of radioactivity and read the data automatically.

Working with these machines, the worm pilot project met its target to sequence three million bases in three years, and established that the technology was scaleable - more money, more machines and more people would produce more sequence faster.

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