By David N. Leff

Smaller than a comma on this page, a lowly roundworm last week became the first animal to have its entire multicellular genome sequenced.

A star-studded press conference, held by the National Human Genome Research Institute in Washington, D.C., last Thursday broke the news that Human Genome Project researchers in the U.S. and Great Britain "have sequenced the 97-million-base genome of the tiny roundworm, Caenorhabditis elegans." The event's press release pointed out that the accomplishment "marks the first time scientists have spelled out the instructions for a complete animal that, like humans, has a nervous system, digests food, and has sex." A day later, the current issue of Science, dated Dec. 11, 1998, made the sequencing its cover story, with a six-article special section and a "News Focus" editorial, reporting, in short, that "the effort to sequence the genome of the nematode Caenorhabditis elegans is essentially complete."

Sequencing Eight Years In The Making

It took eight years for the C. elegans Sequencing Consortium of some 200 worm biologists to assemble the 97 million nucleotides, comprising 19,099 protein-coding genes on six chromosomes in 959 cells, which make up the 1-millimeter-long-by-0.1-millimeter-wide animal.

Their enterprise was led by two longtime C. elegans researchers, one-time immunologist Robert Waterston at Washington University, in St. Louis, and John Sulston, at the Sanger Center of Britain's Medical Research Council, in London. They are the co-senior authors of the lead paper in Science, titled "Genome sequence of the nematode C. elegans: A platform for investigating biology."

Previous such total-genome platforms, between 1995 and 1998, have sequenced only 16 prokaryotic microorganisms - 13 bacteria, three archaea (extremophile bacteria), and one eukaryote, the single-cell baker's yeast, Saccharomyces cerevisiae. However, The Institute for Genomic Research (TIGR), in Rockville, Md. - source of this data - lists another 64 "microbial genomes in progress" on sequencing drawing boards throughout the world.

As for C. elegans, the minute, transparent worm that broke through into the multi-cell league grows to maturity in 3.5 days, lays some 100 eggs per day, and has a life expectancy of two weeks.

In a state of nature, this nematode dwells by the millions in the soil, and eats rotted plant biomass. In research laboratories, it grows in microtiter wells and feeds on E. coli. C. elegans spends much of its short life in hibernation, which can last for months of suspended animation. When the worm wakes up, it starts reproducing. Finding a sex partner is no problem, because the tiny animal is equipped with both male and female procreative organs, permitting self-fertilization.

C. elegans is the white sheep of the nematode family. Many a neurobiologist, biochemist, developmental biologist and molecular geneticist views the lab-inhabiting version as their best friend. But infectious disease specialists and plant scientists wage constant war against the rest of the nematode tribe.

Population biologist Mark Blaxter, at the University of Edinburgh, U.K., authored one of the six articles in Science, titled "Caenorhabditis elegans is a nematode." He made the ominous point that "C. elegans is not the most important nematode on our planet. From the human perspective, the prize probably goes to Ascaris lumbricoides, the large gut roundworm that infects more than one billion people worldwide, causing malnutrition and obstructive bowel disease.

"Close behind," he went on, "are the human hookworms ... that infect more than 600 million today, and were once the scourge of the southern U.S."

And then there is trichinosis, caused by worm-contaminated, undercooked pork. And the plant-parasitic root-knot nematodes, which "cause hundreds of billions of dollars of crop production loss worldwide."

All told, Blaxter pointed out, "although the number of described species of nematode is only about 20,000, estimates of the actual number range from 40,000 to 10 million." And he said the just-announced total sequence of the worm may "yield an improved understanding of other nematodes, so as to enable the development of control strategies to alleviate their effects on human populations."

Although our genome has 3,000 megabases to the worm's 97, humans have a lot in common with C. elegans. It possesses many of the same tissues as Homo sapiens, such as muscles, nerves, skin and gut. Nearly one-third of its 959 cells make up a nervous system that can respond to odor, taste, temperature and touch.

"There are some instances," molecular biologist Elaine Mardis told BioWorld Today, "in which a similar gene in the worm exists in humans. Of course, because the nematode is a much simpler system, we can study the manifestation of this similar mutation in its gene, and hopefully extrapolate that to the human condition."

Gene Substitution And Mutation Studies

Mardis, who directs the technology development group in the Washington University half of the Sequencing Consortium, offered two concrete examples of human/nematode disease applications: "In the case of Alzheimer's disease [AD]," she observed, "early linkage studies in humans showed that there were genes called presenilins. And the only known homologue was found in the C. elegans SPE-4 gene. That stands for 'suppressor/enhancer," she explained, "because it looks like a suppressor or enhancer of secretory function in the worm. The loose association to AD is that somehow the presenilins affect secretion into or out of neurons in that disease. I think the theory is either you don't get secretion of certain proteins out of cells, or you do, and these tend to aggregate and form the plaques and tangles that disrupt neuronal function in AD.

"The other gene," Mardis went on, "Bcl-2, stands for human B-cell lymphoma, where the homolog in C. elegans has to do with the cell-death pathway. The human Bcl-2 gene has been used in place of the homologous gene in the nematode, and reproduced the same effect - the cell-death pathway is disrupted, and the cells don't go through their normal cycle."

AxyS Pharmaceuticals Inc., of South San Francisco, has launched a drug-discovery program in alliance with Roche Bioscience, of Palo Alto, Calif., focused on C. elegans. "Our NemaPharm technology," said the firm's industrial relations officer, David Gennarelli, "uses genetic screens to identify novel targets in conserved molecular pathways that are altered in human disease. The NemaPharm scientific staff possesses over 5,000 genetic strains of nematodes." n

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