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MODEL REQUIREMENTS:
See-through skin // 100,000 progeny in 10 days // A well-mapped anatomy // the ability to effect
“fundamental changes in our understanding of life.”

A Mighty Worm

By Linda Keslar // Illustrations by Linn Olofsdotter // Winter 2009
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The lecture was about jellyfish, but Martin Chalfie was daydreaming about worms. After the speaker described a protein—green fluorescent protein, or GFP—that makes jellyfish glow in the dark, “I got very excited and didn’t listen to another word,” Chalfie remembers. It was 1988, and Chalfie, a biological science professor at Columbia University, found himself thinking about the recently discovered protein: “What a wonderful compound to put into C. elegans.”

At the time, the nematode Caenorhabditis elegans, or C. elegans, had attracted a small, fervent circle of researchers who had come to recognize the worm as a simple model for some of the most complex processes at work in human cells. Transparent and a mere 1 millimeter long, the worm was thought to share many fundamental genetic characteristics with people, though scientists estimated that the species’ evolutionary paths had diverged some 800 million years earlier. But the techniques to explore those similarities had barely been born.

His mind wandering at the lecture, Chalfie envisioned the glowing protein, somehow inserted into the worm and linked to other proteins, serving as a kind of green highlighter marking the tiniest of cellular processes. If he could figure out a way to insert GFP without needing any other compound from the jellyfish, it would be a breakthrough for studying C. elegans and its nearly 1,000 cells, and it would add to the worm’s renown as an ideal model organism for unraveling the mysteries of human genetics.

Chalfie’s hunch proved prescient, though it took several years of painstaking effort to get GFP working in the worm. And his achievement with C. elegans was just one of many. During the past half-century, the nearly microscopic, see-through worm has been so closely observed that scientists have a nearly exhaustive knowledge of its brain, nervous system, digestive tract, musculature and reproductive system. That knowledge, in turn, has greatly expanded the understanding of human systems and processes.

All this groundbreaking worm work has earned its champions three Nobel Prizes during the past six years (including one, in 2008, for Chalfie, who shared the chemistry prize for pioneering the use of GFP), with more likely to come. “C. elegans has led to fundamental changes in our understanding of life,” says Chalfie, who continues to use the worm to study nerve cell development and function. Meanwhile, the community of worm researchers, once almost as diminutive as its subject, has expanded exponentially, with scientists now using C. elegans to gain insight into the mechanisms of aging, Alzheimer’s disease, stroke, cancer, retinitis, diabetes, kidney disease and other disorders.

“The worm poses questions we could never have even thought about without it,” says Robert Waterston, a professor of genome science at the University of Washington’s School of Medicine in Seattle. And the answers keep coming, as C. elegans guides researchers into a previously unimagined universe of regulatory molecules that could revolutionize medicine and drug development.

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A Rich Lineage

Devotees to the worm C. elegans trace their research roots.

Far Away, Yet So Close

C. elegans-assisted breakthroughs in medicine show that the genetics of man and worm are surprisingly similar.

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hed-dossier

1. In the Beginning Was the Worm, by Andrew Brown (Columbia University Press, 2003). Brown, a science journalist, tells the compelling story of Sydney Brenner’s worm project and of the vision, personalities and work of the first generation of worm researchers.

2. “The Perfect Storm of Tiny RNAs,” by Gary Ruvkun, Nature Medicine, October 2008. The 2008 Lasker Award winner details how C. elegans research led to the breakthrough discovery of a universe of tiny regulatory RNAs that were initially considered “worm curiosities” until they were also discovered in plants, and why this worm is important to the future of medicine.

3. wormatlas.org and wormbase.org. WormAtlas describes every cell and tissue of C. elegans and includes information developed for teaching purposes. WormBase houses information about all C. elegans genes and details research in such categories as cell biology, neurobiology, evolution and disease models.

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