Also in This Issue
FEATURES
The Order of the Flies
Brain Detectives
DEPARTMENTS
Front Lines
Research Notes
Notable Results
Re: Action
Hands On
Observations
>> Download entire Fall 2007 issue as PDF.
The Order of the Flies
The behavioral genomics labs at Brandeis are abuzz with discovery
By Laura Gardner
Most people encounter them in the kitchen as tiny, hovering pests that nosh on overripe peaches during the dog days of summer. Drawn to odors from fermenting fruit and vegetables, they seem to make up in vast numbers what they lack in individual size. Reaching adulthood in just ten days and able to lay up to a thousand eggs, they possess a fecundity that is nothing less than spectacular. All this within a life cycle of three fruitful weeks.
Known as "Drosophila melanogaster," fruit flies have been geneticists’ model organism of choice for almost a century, shedding light on some of the most fundamental aspects of human nature.
“The reason people still research Drosophila genetics—and will in another hundred years—is because of the experimental advantages,” says Michael Rosbash, biology professor, Howard Hughes Medical Institute investigator, and director of the National Center for Behavioral Genomics at Brandeis. Rosbash and his colleagues have done groundbreaking work in identifying and studying genes that encode the biological clocks of fruit flies.
“Somebody may come along with something as good as flies that is closer to mammals, but it hasn’t happened yet,” says Rosbash.
Flies are relatively simple from a genetic point of view, yet still possess a rich behavioral repertoire. By manipulating their genes and cells, scientists have been able to unravel some of the molecular mechanisms that drive behavior, says neuroscientist Leslie Griffith.
“I am really interested in human behavior—why we do what we do. What are innate behaviors? What are learned behaviors? How do sensory experiences get translated into behavioral choices?” says Griffith. “By tinkering with neural circuits, you can change flies’ behavior; it is really quite cool, and it’s getting even more exciting because of the new genetic tools coming out.”
Many of the genes discovered in the fruit fly have been validated in mammalian models as well as in humans. With the mapping of the human genome (as well as the fruit fly genome of about 14,000 genes) complete, Brandeis scientists now are able to exploit the advantages of this model organism as never before, in turn raising the curtain on the biochemical basis of behavior in areas such as learning and memory, circadian rhythms, sleep, and perhaps even mental illness.
Lord of the flies
Almost four decades ago, biologist Jeff Hall, who had trained with Seymour Benzer, one of the giants of Drosophila research, came to Brandeis and launched fly studies here. Hall, who is retiring in December, went on to become an international pioneer in the field of Drosophila neurogenetics, helping put Brandeis on the map as a leading center for fly research.
“Jeff Hall has been a critical contributor to whatever my lab has achieved,” says Rosbash of his longtime friend and collaborator. Griffith describes herself as the “intellectual granddaughter” of Hall because she did her early work with a scientist whom he taught.
Rosbash’s and Griffith’s are among eight research labs in the life sciences that make up the National Center for Behavioral Genomics. The interdisciplinary research group was formed in 2004 with congressional funding to tackle fundamental questions about brain function and behavior and to train the next generation of scientists. In spring 2009, the center will move into state-of-the-art laboratories and teaching facilities in the first new building of the 175,000-square-foot Carl J. Shapiro Science Center. Common space, designed specifically to promote faculty and student interaction and collaboration, includes seminar rooms, an atrium, and a science café.
“This building is going to add a structural component to our collaborations, because we’ll be in labs next door to each other with shared equipment, and students will be able to work side by side with faculty other than their advisers,” says Griffith, who researches how neural circuitry drives courtship behavior in Drosophila.
Biologist Paul Garrity researches how fruit flies obtain and process environmental cues to make decisions. He is most interested in the molecules involved in detecting temperature, which, in turn, affect fly behavior. Temperature sensing, which is closely linked to molecular pathways associated with pain and inflammation, is nearly universal among species, controlling everything from geographic distribution to evolution and survival.
Not all of the center’s faculty members are Drosophilists. Sacha Nelson and Gina Turrigiano use mice and rats to study Rett syndrome (see article, page 10), a developmental disorder that causes mental retardation and shares genetic similarities with autism. Neurobiologist Susan Birren also uses rodents to study how disruptions in developmental pathways can contribute to autism at one end of the life span and to Alzheimer’s at the other. Piali Sengupta researches how thermosensory and olfactory neurons in the round worm, C. elegans, recognize environmental cues and respond accordingly.
Behavior-governing molecules
Equipped with powerful molecular genetic tools, these scientists are in search of the molecules that govern behavior. The questions they seek to answer are among the most pressing in biology: How do we learn? How does memory work? What causes depression? Why do we spend one-third of our lives asleep? What are the biochemical bases of Alzheimer’s, schizophrenia, autism, sleep-related disorders, and even jet lag? The center’s ultimate goal is to contribute to treatments and diagnostics for these and other conditions of the mind.
Since 2004, the army has funded one of the center’s most collaborative projects: researching the functions and mechanisms of sleep. “The army has a very long-standing and deep interest in sleep and in its companion, vigilance,” explains Rosbash. “In the military, almost all noncombat and many combat-related deaths are due to fatigue.”
The Army funds basic sleep research because such knowledge is critical to the development of therapeutics that could help fatigued soldiers stay mentally alert, for example, or resist fatigue for a longer time. Over the past several years the army has funded more than $5 million in Brandeis sleep research.
Circadian clockwork
Rosbash has spent more than twenty-five years studying circadian rhythms in Drosophila. Operating in concert with the twenty-four-hour rotation of the earth, primordial circadian rhythms are the molecular machines that internally keep track of time, governing physiology and behavior in virtually every species in the plant and animal kingdoms. Indeed, research has shown that regulation of circadian rhythms at the molecular level is very similar in all animals, including humans.
Rosbash and Hall cloned the first Drosophila circadian clock gene, called period, in 1984. Several years later, they proposed a theory to describe the molecular mechanism, a negative feedback loop by which the twenty-four-hour internal clock works. This is the “quartz crystal” of our cellular watch: key clock proteins are synthesized up to a certain threshold, and then they turn off their own synthesis. These genes in the negative feedback loop cause many cellular proteins to ebb and flow in harmony with the daily light and dark cycles.
“Think of it like an assembly line producing auto parts with a just-in-time supply, so that when the supply of parts exceeds the need for them, the assembly line shuts down. In this way, the negative feedback loop goes from peak to trough, back to peak again in a twenty-four-hour cycle,” says Rosbash.
Having developed a rhythm of its own early on, the Rosbash lab has continued to make steady and pioneering contributions to circadian research. Earlier this year, Rosbash and his colleagues published research findings showing that circadian cells function as a network that enables the insects to adapt their behavior to seasonal changes. The Rosbash lab’s interest in circadian neuronal circuits complements the Griffith lab’s research on this topic, and the discovery on seasonal adaptation might lead to an understanding of how mammals, presumably including humans, adjust their physiology and behavior to short winter days and long summer ones. This work may, for example, provide some insight into winter depression.
Fly brains are beautiful
Griffith’s lab most recently has been researching the chemical cues, known as pheromones, that drive romance. Flies (like humans) ritualize romance; their rituals include singing and licking before mating.
“What flies do in choosing a mate and how males and females interact are very reminiscent of human behavior,” says
Griffith. “Male flies have a very strong drive to reproduce, as do females, and that drive, if inappropriately expressed, can lead to wasted time and therefore reduced fitness. They have to learn to court an appropriate object, as do human beings. In flies, that learning takes place very quickly. It’s based both on the male’s experience and the chemical cues that the female gives off.”
If the past hundred years of fly research has been fruitful, the next hundred years promise to be exponentially more productive. But at the heart of all successful research are the drive and imagination of the researcher.
As Griffith sums up, “Fly brains are beautiful. I love fly brains, but on the other hand, my curiosity is driven by the fact that I am human.”