Lord of the Flies : Caltech Professor’s Mutant Insects Yield Key Clues to Cell Development
Fruit Fly is a tiny brown creature with bulging polyhedral eyes. He doesn’t like dirt. If a microscopic piece of mold clings to his back, a pair of bristly legs swivel around and push it off.
There is a pristine simplicity to Fruit Fly, says Edward Lewis. The insect is clean, disease-free and, in its normal form, an exact replica of all of its relatives. “There isn’t that crazy variability that you see in some creatures,” says the Caltech biology professor.
Lewis, 71, has been studying common fruit flies, mainstays of genetics laboratories, precisely because of that consistency in form, for more than 50 years.
A short, unassuming man with neatly clipped white hair, Lewis is one of perhaps 100 microbiologists and geneticists around the world--popularly known as the “Lords of the Flies”--who have made Drosophila melanogaster their life’s work.
Sound ridiculously esoteric? Hardly. The tiny flies, about an eighth of an inch long when they’re fully developed, are providing answers to some of the big questions about organic development: How does a blip-like aggregation of cells develop into a complicated organism, with eyes, gonads, a nervous system and the rest? What can go wrong? What causes cancer or birth defects?
Lewis’ little flies (you’ve seen them swarming around overripe bananas) have been providing the stuff with which to delve deep into the peculiar chemistry of life.
Lewis, who is widely acknowledged as one of the preeminent “Lords,” was recently elected to the Royal Society of London (Isaac Newton was an early president). His speculations 30 years ago about the existence of clusters of developmental genes, forming a kind of “command center” to direct other genes, helped set the agenda for recent genetics research, some of his colleagues say.
“Ed’s probably the seminal figure in the field,” said Yale University molecular biologist William McGinnis.
Lewis usually speaks in the sober, measured tones befitting an internationally recognized scientist, with digressions about the “ultrabithorax gene” or the roentgens produced by background radiation. (A roentgen is a measurement of radiation named for the discoverer of X-rays, Wilhelm K. Roentgen.)
Even his colleagues can stumble trying to keep up. “He has an immense library of information inside his head, much of which hasn’t been published,” said University of Colorado molecular biologist Matthew Scott. “He’s in a world of his own, which is not easily penetrated.”
But Lewis can be downright rhapsodic when he talks about his flies.
On the third floor of Caltech’s Kerckhoff Hall is a refrigerated room, maintained at 68 degrees Fahrenheit, with shelves brimming with jars, like small milk bottles. There are about 8,000 of them in the “Cold Room,” and they hold a revolving population of about 2 million flies.
Lewis sprays some ether into one of the jars, shakes a few specimens onto a piece of glass and slips it under a microscope. The flies, knocked out but trembling faintly, leap into magnified focus. “They’re quite pretty,” said Lewis, unable to suppress a smile. “The color of the eyes--beautiful, really.”
The wings are diaphanous, the legs hairy. The eyes are like multifaceted goggles, dabbed with reddish pigment the color of canned tomato soup.
Drosophila is a perfect laboratory specimen, says Lewis. “They keep themselves scrupulously clean,” he said. “They acquire no known diseases. All of your (fruit flies) can’t get wiped out at once by some sickness. That’s happened with mice, you know.”
Even more important for the geneticist is the flies’ lack of individual differentiation. “There is a real ‘normal animal,’ ” said Lewis. With more complicated laboratory specimens, individual differentiation makes it difficult to say what is really normal. The point is that geneticists and microbiologists learn about the normal by studying the abnormal.
A weekly event in the basement of Kerckhoff Hall is the mutating of male flies with X-rays. About 30 of them at a time are etherized and packed into a gelatinous container, like a big vitamin capsule, and zapped with X-rays.
“We give them a dose which would kill a human being outright,” said Lewis. “It’s about 10 times the lethal dose.”
The resilient fruit flies’ bodies come through almost unscathed. But their chromosomes, the coded genetic material that dictates the form of their offspring, are often disrupted by errant electrons. Chances are that the sons and daughters of those irradiated male flies (which are bred with virgin females) will be mutants.
In the Cold Room, there are jars full of flies with legs growing out of their heads where antennae should be, eyes without pigment or extra sets of wings. These are the freaks that provide signposts to the essence of the normal.
“What the geneticist has to do is use mutation to figure out the normal,” said Lewis.
New Techniques
Comparing normal and abnormal specimens, Lewis and his post doctoral fellow Sue Celniker have mapped specific genes on oversized chromosomes from the flies’ salivary glands. (“They’re a thousand times bigger than ours,” said Lewis.) Using new chemical techniques, they have begun to identify the specific proteins that carry developmental messages to embryonic cells.
The pristine simplicity of Fruit Fly has yielded some intriguingly simple truths about the development of an organism, says Lewis.
“There are clusters of genes on the chromosomes lined up in the same order as the flies themselves,” he said.
In other words, if you could “read” particular clusters of genes strung out along a chromosome, they would spell out the body of Fruit Fly, in the sequence in which it normally develops: head, abdomen, thorax. After one segment develops in its embryonic state, the associated developmental cluster turns itself off (or switches modes) and flips on the next one.
Repeated Developments
Disrupt the process, however, as with an X-ray-induced mutation, and a peculiar thing happens. Development gets stuck in a particular mode. Thus, the wing segment, for example, repeats itself, giving Fruit Fly multiple sets of wings instead of the normal pair.
The wider significance of the odd behavior of fly chromosomes is the possible link between cancer (in which cells replicate themselves irrationally) and genetic defects. “Cancer is really a return to the embryonic cell state,” said Lewis, “with cells that aren’t under master regulatory control.”
Other geneticists have actually isolated a cluster of cells that appear to serve as the developing organism’s command center, turning developmental genes on and off at precisely the right moments. The same cluster, called the “homeo box” (from the Greek homeotic, meaning similar) has been found in fruit flies, frogs, mice and humans.
An amazing discovery, says Lewis. “It shows (humans and lower life forms) have a common ancestor, going back more than 500 million years,” he said. Twenty-nine years ago Lewis predicted the eventual discovery of the master regulatory genes, which dictate the course of development from embryo to mature organism.
Lewis compares the homeo box to a computer on a modern fighter plane, keeping the speeding machine stable and flying in a straight line. “The master control regulates all the parts,” he said. “There’s a core of information sitting there, like the genes in the homeo box.”
‘Homeo Madness’
For the last three years, the homeo box has been the hottest thing in genetics. Its discovery--Scott and McGinnis, working independently, can claim credit--has started a wave of “homeo madness,” as one journal put it, with one scientist after another weighing in with new findings.
No one is sure yet what happens when there are disruptions of the homeo box. “But there are all sorts of problems due to slight losses (in genetic material),” said Lewis, citing the recent discovery that cystic fibrosis occurs because of the absence of just three of 250,000 chemicals composing one human gene.
Lewis’ obsession with Fruit Fly began when he was a teen-ager in Wilkes Barre, Pa. “There was an advertisement in Science magazine saying that you could buy fly cultures,” he said. By the time he and a fellow student began growing their own flies in the high school biology lab, they had both read “The Biological Basis of Human Nature,” by Herbert Spencer Jennings, and they were brimming with new ideas.
Why the passionate interest? “I think it was that you could, with a few symbols, express how things are inherited,” said Lewis.
Work of Predecessors
He went to the University of Minnesota--”It was a big university that didn’t charge much money for out-of-state students”--and got his doctorate from Caltech in 1942. He has been a fixture at the institute ever since, carrying on the Drosophila work of his predecessors at Caltech, Thomas Hunt Morgan and Alfred H. Sturtevant.
The fruit flies that Lewis experiments with are the descendants of the fruit flies brought to Caltech by Morgan in 1928.
Lewis published his first paper on the fruit fly in 1945. That was eight years before the discovery that molecules of DNA (deoxyribonucleic acid) in all organisms carry genetic blueprints. His latest paper (co-authored with Celniker), on the molecular genetics of one of Drosophila’s segments, will be published later this year.
Lewis retired from teaching last year. But he’s not about to stop his research, he says. When he talks about recent developments in genetics, there’s still a whiff of youthful enthusiasm, reminiscent of the high school student from Pennsylvania. “Amazing,” he says frequently.
He gets to the office every morning at 7, unpacks his flute and practices a piece from a stack of music on a table. The other day it was a Poulenc flute sonata. Lewis played it nimbly, with an elegant vibrato on the long notes. The vibrato is a technique he learned only recently, he says.
Then it’s off to the Cold Room to see what Fruit Fly will reveal today.
Someone wrote that the newly discovered developmental genes that Lewis and colleagues are studying represent the Rosetta Stone of organic development. True? “A nice expression,” Lewis said cautiously, switching from artist to scientist. “It sort of gives you the idea.”
