That's sort of what our goal is," remarks Dr. Nancy Bonini, "to address the problems of human disease and the fundamental issues of human development and neurodegeneration." It's a large and ambitious claim. Bonini is an assistant professor of biology who conducts genetic research on the third floor of the Leidy Laboratories. What really makes her claim peculiar though, is the absence of human subjects. Except for a postdoc or undergrad afflicted with a bad case of the sniffles, there's not a sick person anywhere in sight of the test tubes, beakers, and pipettes that festoon the shelves of her research facility. In her lab, Bonini studies Drosophila melanogaster--fruit flies.

The gulf separating Drosophila and Homo sapiens makes it hard to understand how study of the former could yield significant insights into the latter--unless, of course, you consider the micro level of structures and processes probed by molecular biologists. "The genes between flies and humans are remarkably conserved," Bonini declares. Her words are delivered in sober and measured utterances, but her adverbs have exclamation points. "In fact, the more they sequence the human genome and the fly genome, the more it becomes apparent how amazingly fundamental that similarity is. Genes are so fundamentally conserved that we can really use the fly as a model for the human system." Apparently the grant givers agree. Bonini receives funding from the National Eye Institute, the John Merck Scholars Program in the Biology of Developmental Disabilities in Children, the Alzheimer's Foundation, a March of Dimes Basil O'Connor Award, as well as other sources.

The fruit fly has long been geneticists' experimental animal of choice, and not just because of the degree of conservation in the genomes of people and flies. Drosophila has a short life cycle, growing from egg to adult in only ten days. Researchers can knock out genes and then breed and study hordes of these insects, tracking mutant genes across generations in a few weeks. And genes exhibit no respect for the taxonomies that scientists devised to classify the forms of life: it's possible to remove genetic material from one species and implant it in the other. Using the techniques and tricks of genetic manipulation, Bonini has been able to produce transgenic flies--flies that express a particular human gene in every cell of their body.

In one project, Bonini investigated the genetics and molecular biology of eye formation in the fruit fly. In this approach, cloning techniques and methods for determining the expression patterns of genes are applied in experiments to help understand the function of genes thought to be important in the development of fly eyes. Bonini has identified and studied a new gene in Drosophila that regulates the growth of progenitor eye cells, embryonic cells that are forming even before you can tell they're going to become eyes. In flies bred without the eyes absent gene--flies in which the gene has been knocked out--the insect's large compound eyes do not grow, but all other aspects of the organism develop normally. Without the gene, instead of initiating eye cell differentiation, the progenitor cells die, cutting off the pathway that leads to the growth of countless and intricately configured cells that comprise an eye.

"Once a new fly gene that plays a part in eye development is found," explains Bonini, "we try to isolate the human counterpart to see if that gene is conserved." She has removed the eyes absent gene from mice and transplanted it into the eggs of a strain of fruit flies that had been bred without the gene. The flies hatched with a healthy pair of fully functioning eyes. The fact that eye development was restored in the mutant flies strongly hints that the eyes absent gene performs the same function across species. "Recently," she observes, "we found many human genes that are remarkably identical in protein sequence with the fly's eyes absent gene. These human genes are expressed during eye development, suggesting that there may be a family of eyes absent genes in humans that are critical for eye development and function, just like their counterpart in the fly." How the transplanted genes rescue eye development in the mutant flies will be the subject of further study in her lab. Bonini believes this discovery and the subsequent investigations could have future applications for the treatment of eye diseases.

A second project underway in her lab involves using the fruit fly as a tool for teasing out the genetic machinery responsible for certain forms of human brain disease. The techniques and expertise she developed investigating eye genes are used to study defective human genes that cause pathologies in organs other than the eye. Teaming up with researchers from Penn's Medical School, Bonini acquired the gene that causes Machado-Joseph disease (MJD) and implanted it into Drosophila to see if it was possible to breed flies that display a pathology similar to humans afflicted with the disease. Because the fruit fly is less complex, it is easier to track the cascade of biochemical events unleashed by a gene's functioning in the architecture of Drosophila than in the intricate neural labyrinth of the human organism.

Machado-Joseph disease (MJD) is a hereditary neurodegenerative illness that typically strikes in mid-life and produces severe ataxia, an inability to control muscular movements. The progressive symptoms include loss of balance, twitching, slurred speech, difficulty swallowing, loss of eye movement, and deterioration of muscle mass. There is no treatment or cure, and the disease is fatal. MJD is of the same class as maladies like Huntington's, Parkinson's, and Lou Gehrig's diseases.

Over the past several years, "trinucleotide repeat expansion" has been identified as the genetic flaw responsible for a growing number of these progressive, late-onset, neurodegenerative diseases. In each of these disorders, instructions for producing the amino acid glutamine are repeated excessively in a coding region of the DNA. Normally, the sequence of three nucleotides that constitute glutamine--cytosine, adenine, and guanine (CAG)--is repeated 15 to 20 times. In those stricken with Machado-Joseph disease, the CAG sequence has been found to repeat as many as four times the normal number. The result is an abnormal agglomeration of protein in the cell nuclei of the brain, culminating in the degeneration and death of neurons. The brain's precise, light-speed circuitry is disrupted by these protein blobs: neurons misfire; electrical pathways are rerouted or shut down. Body movements too become random, diffused, increasingly chaotic--responding to the outbreak of lightning storms consuming the brain.

"Our hope was that by studying the disease in flies, we could speed along the genetic research in humans," says Bonini. "The advantage of the flies is that we can essentially give them polyglutamine-repeat disease in just ten days. If we could get anything that looked like the human disease, we could then use the flies to get suppressers and figure out how we could treat these diseases." Her experiments succeeded in producing mutant flies with the characteristic globs of protein in the insects' brain cells, confirming that Drosophilia has the fundamental mechanisms by which the affliction proceeds in humans. "Another reason why the fly is an unusually powerful system is that it has a complex nervous system just like we do. It has brain centers composed of multiple cells, and it is capable of very complex behaviors."

Bonini is now using Drosophila to identify the genetic systems and pathways involved in the progression of MJD and to hunt for suppresser mutations that might prevent or delay it. She believes it may be feasible in ten years to have a pill that prevents brain degeneration brought on by polyglutamine-repeat diseases. In the fall of 1997, the Packard Foundation recognized Bonini as one of the most promising science researchers at an American university and awarded her a grant to continue this research.

In the movie The Fly, a scientist is turned into a monster of sorts when a fly's genetic material gets mixed into his genes during a teleportation experiment. When we consider the implications of genetic engineering, the image of some misbegotten creature is often summoned up, and it inhabits our collective nightmare about the on-rushing future. The movie--and the nightmare--suggest an expectation of retribution for science's hubris and illicit tinkering in realms reserved for the gods alone. But contemporary research is revealing that the genetic stuff that makes up the engine of life is already intermingled.

"Almost every day," Bonini notes, "you read in the top science journals of another gene that is cloned in humans, and it's identical to the fly gene. Subsequent studies show that they work the same. We look at the fly and we look at ourselves, and we seem quite different. Maybe there are a lot more similarities than we think: maybe a lot of the differences have only to do with how the expression of genes is regulated at certain times and in certain places. The same complex of genes is being used for eye development in humans as is being used for eye development in flies, and yet there are many, many differences between our eyes and the fly's. To me, it's really phenomenal."

Dr. Randy Pittman, chair of the Graduate Group in Pharmacological Sciences at Penn's Medical School, is one of Bonini's research collaborators who studies the effects of trinucleotide-repeat maladies in humans. He points out that Bonini's "work has provided a powerful approach for understanding the underlying mechanism of neural degeneration in triplet-repeat diseases. By developing the first model of a human neurodegenerative disease in a genetically powerful organism like Drosophila, the impact of her work goes well beyond the seven to eight known triplet-repeat diseases. It sets the stage for investigators to develop models of other neurodegenerative diseases like Alzheimer's or Parkinson's."

Some people might see a world in a grain of sand; Bonini sees the cure for diseases in the eye of a fly. Mixing fly and human genes, she is like the scientist in The Fly. "All along we've been praying that the fly would be a good model," she says, "and time is showing that it's a much better one than we ever hoped it would be." On websites that counsel and support MJD sufferers and their families, there are links to news postings reporting on progress in her research. Nancy Bonini doesn't make Frankenstein monsters; she creates hope for those who suffer.