When Sydney Brenner, one of the founders of molecular biology, chose a worm as a model for studying the nervous systemand, by extension, the human brain"people thought I was crazy," he recalls. But it proved to be a brilliant choice.
Soon after Brenner began these studies in 1965, a small band of scientists from various parts of the world joined him in his efforts to pry out the secrets of the slithery nematode Caenorhabditis elegans. They called themselves "worm people." Their successesand their numbersgrew. By December 1998 they had succeeded in sequencing the entire genome of C. elegans, 97 million base pairs of DNA (genome.wustl.edu/projects/celegans/). This was the first time anyone had access to the complete instruction book for making an animal.
Never mind that the worm they studied is only one millimeter long and almost invisible to the naked eye. What matters is that it is made of hundreds of cells working in unison. Unlike bacteria, yeast, or other single-celled organisms, C. elegans has muscles, nerves, sexual organs, and guts. It reacts to touch. It can recognize smells. And it does all this with only 19,099 genesroughly one-half the number of genes estimated in a human being.
"Why the worm? Why is the Human Genome Project involved in this?" asked Francis Collins, director of the National Human Genome Research Institute, part of the National Institutes of Health (NIH) in Bethesda, Maryland, at the press conference announcing the C. elegans sequence. To find clues to the functions of newly sequenced human genes, he explained. "With the lowly roundworm," Collins said, "we knew we could get the biggest bang for the buck." Both NIH and the Wellcome Trust of London provided financial support for the project.
Work on the worm genome has brought new insights into the mechanisms of Alzheimer disease, stroke, cancer, retinitis pigmentosa (a genetic disorder that causes blindness), diabetes, kidney diseases, and several other disorders.
"The only reason we know anything about what the presenilin genes do in some people who have Alzheimer disease is that we found similar genes in the worm," points out Robert Waterston, director of the Washington University Sequencing Center in St. Louis, which collaborated with the Sanger Centre in Cambridge, England, to sequence the worm's genome.
Early-onset Alzheimer is often caused by changes in a single human gene known as PS1 (presenilin gene number one). After this gene was isolated biochemically in 1995, it was shown to be similar to four other genes, three of which are also found in C. elegans. Researchers at Columbia University in New York City then substituted the human PS1 gene for a similar gene in C. elegans and showed that the human gene works well in the worm. At this news, a large number of researchers in academia and the biotech industry began to study the corresponding worm gene in the hope of finding new therapies for Alzheimer.
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This C. elegans larva will be just one millimeter long when fully grown. Its head is on the right.
Photo: Erik Jorgensen