The first mutant fruit fly on record is a white-eyed fly that the legendary Thomas Hunt Morgan spotted in his "fly room" at Columbia University in 1910. But as early as 1907, Frank Lutz of the Carnegie Institution was remarking to his friends that his flies had "started to do tricks with their [wing] veins" (the prominent veins that form patterns on their wings), and in 1908 he observed dwarf flies among his cultures.

Since then, fruit fly mutants have proliferated like, well, flies, spawning an entire field of biology in the process. There are mutants with bizarre eye colors—pink, purple, maroon, or even vermilion instead of the normal brick red—and those with truncated wings, or miniature wings, or no wings at all. There are mutants that are very hairy and mutants that are bald.

There are giant embryo mutants and mutants with legs growing where their antennae or mouth should be. There are mutants with perfectly formed, functional eyes growing out of their wings, or on their legs, or at the tips of their antennae. There are mutants with two sets of wings instead of one, and mutants with no heads but two abdomens stuck end to end.

There are uncoordinated mutants and mutants with no memory. There are mutants that are hopeless at courting and others that court only their own sex. There are mutants that can't hold their alcohol. And these are only a tiny sample of mutant fruit flies.

By the end of the 1980s, fruit fly researchers—known as "fly people" or "Drosophilists," after the insect's Latin name Drosophila melanogaster—had catalogued some 3,000 different mutations, representing an extraordinary wealth of biological information. This value derived from a simple fact of genetic research: "The way you find out what a gene does," says Hermann Steller, an HHMI investigator and neurobiologist at The Rockefeller University, "is by generating a mutation and looking at the consequences—looking at what the fly does when that gene loses its function. If you had no idea what a car engine was doing or how it worked, you'd take out different parts to see what happens. This is the basic logic geneticists use to see what function genes have."

Over the course of a century, the fly people claim, this wealth of mutants has taught biologists more about the fundamental biological, developmental, and genetic processes of flies than about those of any other single complex organism. (Some researchers would argue that they know at least as much, if not more, about the roundworm C.elegans.) Drosophilists can now describe with a reasonable degree of precision how a fruit fly embryo is put together: what genes turn on when in the course of its development, what those genes do, and why they do it.

All this knowledge would have been of interest only to a small group of specialists except for one thing. The fruit fly work helped spark a revolutionary understanding in biology: that the fundamental genetic mechanisms of development appear to be the same in all living things. Once evolution stumbles upon a mechanism that works, says Matthew Scott, an HHMI investigator at Stanford University, it uses it over and over again. As a result, research on the genome of D. melanogaster is playing a pivotal role in uncovering biological processes that all organisms share.

"If you just have the sequence of the human genome," says Gerald Rubin, vice president of HHMI and professor of genetics at the University of California, Berkeley, who has been working on D. melanogaster for 25 years, "you won't know how to interpret it. It's written in a foreign language that you can't read. What you need to interpret it are the genomes of model organisms, in which people have already done a lot of work to determine what the functions of the genes are.

"You can't do the kind of experiments in humans that you can do in the model organisms. You can't say, 'I want to cross that person with that person and see what their grandchildren are like.' So you have to go back and look in these other genomes for clues to how the human genome works."

Researchers have been cloning the genes of D. melanogaster, one gene at a time, since the mid-1970s, when recombinant DNA technology first became available. But the fruit fly—despite its apparent simplicity compared with humans—is still an extraordinarily complex organism.

"Biological organisms don't work just one gene at a time," Rubin says. "The genes interact with each other in very complicated pathways and networks. We've tended to oversimplify biology to fit what we could work on in the laboratory. We've had some successes. People have figured out development in the early Drosophila embryo, for instance, but that's probably about the most complex thing that we have figured out with this one-gene-at-a-time kind of approach.

"The genome projects are really going to change biology and the way we do experiments. They will allow us to look at the problems in all their complexity and collect all the information we need to approach them at that level."

— Gary A. Taubes

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Gerald Rubin, a leader in the effort to decode the fruit fly genome, stands before a small section of the completed sequence.

Photo: Paul Fetters

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