One of the great revolutions in modern science rests on the elongated backside of a grotesque, mutant worm. Inexpensive and easy to manipulate in the lab, Caenorhabditis elegans develops from egg to adult in three days and produces a few hundred offspring three days after that. Virtually all of the worms are hermaphrodites, containing both male and female sex organs and capable of making sperm and eggs, so each creature can fertilize itself. And because the worm is transparent and the adult has only 959 cells, development of every stage from egg to adult can be observed under the microscope and documented with near perfect detail while the worm is alive, an achievement accomplished in the 1970s by Sidney Brenner, a University of Cambridge researcher and legend in the field.
C. elegans has been a favorite in biology labs for years due to its transparency, speedy reproductive cycle, and ability to mutate on cue. Just irradiate it or add chemical mutagens to its petri dish, then wait a few days to see what kind of freak worms appear in the progeny. In the late 1970s and 1980s, “worm talks” (as C. elegans lectures were called) inevitably began with a description of development in the normal worm and segued to whatever mutants the lecturer found intriguing.
The “bag of worms” was one such mutant. This version of C. elegans has the singular misfortune of being unable to lay the eggs that it fertilizes. It gets stuck in the earliest stage of wormy development, making the same larval cells repeatedly while failing to form the organs and body parts needed for later life—including the vulva required to get the eggs out of its body. The result is an oversize larva filled with dozens of offspring, hence its nickname. But it does not remain in that state for long. “The eggs hatch inside the worm, and the larvae consume the mother and crawl away,” Victor Ambros, a biologist at the University of Massachusetts, explains.
Ambros first heard about the bag of worms at a 1979 lecture by Robert Horvitz, who had studied C. elegans in Brenner’s Cambridge lab. At the time, Ambros was finishing up a doctoral degree at MIT, studying with Nobel laureate David Baltimore. A few months later he began a postdoctoral fellowship with Horvitz, who suggested he try to identify the defective gene responsible for the grotesquery that was the bag of worms. What followed in fits and starts over a quarter century has evolved into what Baltimore now describes as “a whole new biology.”
It took Ambros 13 years to identify and sequence the defective gene responsible for generating the bag of worms mutant from a normal C. elegans mother; located on chromosome 2 within the worm’s genome, the mutant gene was named lin-4. As it turned out, the gene coded not for a protein—as all genes were then thought to do—but for a tiny snippet of RNA, the simpler molecular cousin of DNA. The RNA molecule was one-hundredth the size of a gene encoding a typical protein, so small it was hard to imagine its having any function whatsoever, let alone producing a mutant as dramatic as the bag of worms.
