Hook, line and model: Scientists use fruit flies and worms to fish for biological treasure

CAMBRIDGE, Mass. — Hamlet provided one of the zippiest summations of the connections among life forms: “A man may fish with the worm that hath eat of a king, and eat of the fish that hath fed of that worm.” Of course, fishing with flies hath also been popular. The flies and worms in this story differ from those preferred by fisherfolk. Nevertheless, these Lilliputian creatures have caught some big ones; most of what we know about genetics, genomics, and development can probably be credited to this one fly and one worm.

The organisms in question are the old laboratory workhorse, the fruit fly Drosophila melanogaster, and the newer, but no longer new, kid on the block, the soil nematode Caenorhabditis elegans.

The meek really did inherit the world of biological research. The male fruit fly is about 2 millimeters long, the female about 3. The worm is about 1 millimeter long and there’s no need to divvy that figure up further by sex because they’re hermaphrodites. (Okay, one in 700 is a true male, the odd man out.) They have brief lives and they fly/crawl under the radar of people who ordinarily take umbrage over animal research. They’re the perfect guinea pigs, much better than, well, guinea pigs.

One of the worm’s key qualities is that “it was small enough for slices to fit under an electron microscope,” Andrew Brown writes in his C. elegans history, In the Beginning Was the Worm. The transparent nature of C. elegans made it a window for John Sulston, who in the 1970s painstakingly traced the appearance of each of the 959 cells that constitute a complete worm. He saw an additional 131 cells that come into being and then self-destruct as the worm molds itself into its final form. The lab also produced a complete diagram of the connections among the worm’s 302 nerve cells.

Meanwhile, one of the unusually visible things about fruit flies is their honking big chromosomes. In many cells, notably in the salivary glands, chromosomes keep getting copied and line up neatly together, but the cell doesn’t divide. The result is a big, beautiful “polytene” chromosome with a distinctive banded appearance. “Those chromosomes were really important for providing a physical map, visible under the light microscope,” says Terry Orr-Weaver, a Member at Whitehead Institute and MIT professor who studies links between development and cell growth and division. Those giant DNA strands have, for almost a century, given researchers a peek at the hereditary material they ordinarily study indirectly, usually by mucking with the genes and following the freaky effects.

The results often are quite dramatic. Antennapedia mutant fruit flies get a leg up—up on the top of their heads, in fact. Such mutations shed light on the genetic sequences that govern fundamental genetics of development, in flies and us. Famous C. elegans mutations tend to be less Frankensteiny, but one gruesome one is known as bag o’ worms. The hermaphroditic worm self-fertilizes its eggs, but in this mutation the organism can’t expel them. The eggs hatch in the parent and, as Brown puts it, “with nematode pragmatism, eat it alive, from the inside, until they can burst out.” And, because this is a heritable mutation, the same thing happens to the perpetrators when they mature in a few days. It’s Oedipus and Electra all wrapped up in one tiny, clear package

Each organism has its patron saint. Almost a century ago, Thomas Hunt Morgan was looking for good research animals with which to study evolution. Drosophila literally flew in Morgan’s window at Columbia University in New York City.

Morgan initially hoped to study evolution, and tinkered with some 50 species. Gregor Mendel may have glimpsed the first, simple rules of heredity working with peas, but it was Morgan’s fruit flies that would spill the beans.

Mutations are rare. But flies, producing large numbers of offspring in short amounts of time, eventually popped out a few obvious ones. Tracking mutations over generations meant producing more offspring, which led to more mutations. Robert Kohler, author of Lords of the Fly, a history of the early years of Drosophila research, writes that fruit flies had become “a biological breeder reactor, creating more material for new breeding experiments than was consumed in the process.” Morgan, who got his Nobel Prize in 1933, was a smart guy—he realized that his research subject was dictating the experiment, and he quickly mutated himself from an evolutionist into a geneticist.

Sidney Brenner, at the Laboratory of Molecular Biology, in Cambridge, England, on the other hand, made a concerted effort in the 1960s to find a suitable organism for his almost mind-numbing purpose, which was basically to find out everything possible about how a specific multicellular organism works. Fruit flies were too complicated for that ambition. In a proposal to the Medical Research Council, he wrote, “To start with we propose to identify every cell in the worm and trace lineages.” And that’s exactly what he and other researchers, including Sulston and Robert Horvitz, now at MIT, did. Except that the worm turned—the species in the original proposal was C. briggsae. Shortly thereafter, Brenner switched to C. elegans. It was a good choice, with the three sharing a 2002 Nobel Prize.

Drosophilists, with a 50-year head start, still outnumber elegansers: 1,662 people subscribe to Flybase, a Web site devoted to all things fruit fly, whereas Jonathan Hodgkin, an early member of the Brenner lab, reported in January that 479 scientists were registered with the Caenorhabditis Genetics Center. Everybody plays nice now, but there have been minor turf tensions between the two communities. “They’re fruit flies that don’t pupate,” was how a Drosophila researcher once disparaged C. elegans. But the worm had the first laugh; in 1998, it became the first multicellular organism to have its entire genome sequence published. Drosophila had to wait until 2000.

“The topic should not be considered as C. elegans vs. Drosophila but rather as C. elegans plus Drosophila,” says Horvitz, who got his Nobel for figuring out the genetics behind apoptosis in worm development and discovering analogous processes in us. “It is the combined analysis of these two highly tractable experimental animals that has provided and that will continue to provide repeated breakthroughs in basic biology and insights important for the field of biomedicine.”

Indeed, insights from the two organisms have revealed that there has been a remarkable conservation throughout history of basic genetic systems: Studying flies or worms thus often is an efficient way to study ourselves. Orr-Weaver was at a meeting at which fly guy Gerald Rubin cited the implications of this gene conservation by saying, “When you see the fly, you should think of little people with wings.” “Then,” Orr-Weaver recalls, “someone in the audience said, ‘Gerry, I think those are called angels.’”

For more information, visit Flybase at www.flybase.org and Wormatlas at www.wormatlas.org.