It started with worms that would not grow up. In early 1990s, Victor Ambros and his colleagues were conducting a gene hunt. In particular, they were searching for gene that was mutated in a perplexing strain of Caenorhabditis elegans, small nematode whose development many biologists study. This genetic change Ambros hunted had apparently disrupted worms' developmental timing. In normal strains, worms pass through four larval stages as they mature into fertile adults. But members of mutant strain get stuck at first stage. They would molt, but instead of moving on to second larval stage, they simply repeated first stage. The larvae kept growing larger but never became fullfledged adults. Ambros' team painstakingly homed in on gene responsible by adding pieces of DNA from normal C. elegans back into mutant worms. If a DNA sequence restored full development, it presumably harbored a working copy of gene that's defective in mutants, reasoned investigators. In 1993 at Dartmouth Medical School in Hanover, N.H., hard work of Ambros and his colleagues paid off with elusive gene's discovery. It was a heroic detective story, says Sean Eddy of Howard Hughes Medical Institute at Washington University in St. Louis. The story had a surprise ending, too. Unlike most genes, one identified by Ambros' group doesn't encode a protein. It spawns a small molecule of RNA-a chemical relative of DNA-that somehow turns off other genes that play a role in worm development. This odd finding stood alone until a few years ago, when a team led by Gary Ruvkun of Massachusetts General Hospital in Boston found a gene that controls C. elegans' transition from fourth larval stage to adulthood. This gene also creates RNA that regulates expression of worm Although Ambros hadn't found genes in other organisms similar to one he'd identified in C. elegans, Ruvkun and his colleagues discovered that many animals have versions of this second RNA-encoding worm gene. His team found such genes in flies, mollusks, fish, and even people. The researchers speculated that RNA produced by gene is a universal regulator of animal development, perhaps an important controller of a caterpillar's metamorphosis into a butterfly and a tadpole's into a frog. Inspired by such research, biologists have now begun to systematically look for so-called RNA genes. DNA whose final product is RNA instead of protein. Several groups, including one led by Eddy, recently surveyed DNA of bacterium Escherichia coli and uncovered dozens of such Just a few months ago, Ambros' team and two other research groups reported that worms, flies, and people contain dozens of previously undetected genes that spawn RNA instead of protein. These investigators argue that many intensive searches for protein-coding genes have ignored or missed genes for small, stable RNA molecules that have cellular functions. The RNA genes found so far are just tip of a huge iceberg, says Ruvkun. The biologist goes as far as to compare RNA-gene findings to a humbling discovery on a much larger scale. Astronomers studying effects of gravity on galaxies found to their astonishment that universe contains large quantities of so-called dark matter, mass that still eludes observation. In Oct. 26, 2001 SCIENCE, Ruvkun speculates that the number of genes in tiny RNA world may turn out to be very large, numbering in hundreds or even thousands in each genome. Tiny RNA genes may be biological equivalent of dark matter-all around us but almost escaping detection. RNA genes have already attracted commercial interest: A biotech firm is testing whether some of newfound bacterial RNAs play a role during infection and might therefore be targets for new antibiotics. If that's not provocative enough, some scientists suggest that RNA regulation of gene activity and other cellular processes could explain diversity and complexity of plants and animals as compared with bacteria.