Molecular Biology, Neuroscience
Dr. Rosbash is also the Peter Gruber Professor of Neuroscience at Brandeis University.
Circadian Rhythms, Neurons, and Sleep
Most scientists spend their careers exploring the depths of one specialized field. For more than 25 years, Michael Rosbash has divided his time between two and made significant contributions to both. His studies of the metabolism and processing of RNA have uncovered some of the fundamental steps by which this key molecule carries out the protein-building instructions written in genes. In separate work, Rosbash also has helped to reveal the molecular basis of circadian rhythms, the built-in 24-hour biological clock that regulates sleep and wakefulness, activity and rest, hormone levels, body temperature, and other important functions. Using the fruit fly Drosophila as a model, he has identified genes and proteins involved in regulating the clock and proposed a mechanism for the way it works. Rosbash's discoveries apply not only to insects but also to humans and other mammals, and they ultimately could lead to the development of drugs to treat insomnia, jet lag, and other sleep disorders.
Rosbash's interest in RNA processing began as a graduate student at MIT in the mid-1960s. Watson and Crick had cracked the genetic code the decade before, and scientists were keen to learn more about the role of RNA. Through the years, Rosbash's studies have helped to clarify the process that begins when RNA is transcribed from DNA in the cell's nucleus and ends in the assembly of a finished protein in the cell's cytoplasm. Enzymes, proteins, and subcellular organelles all converge upon RNA in precise order as it is translated into proteins, his research shows. Missteps in the process have been linked to diseases, including certain cancers, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease. "The more we understand the players, the more likely we can fix what goes wrong," says Rosbash.
His interest in circadian rhythms was sparked by a friendship. After Rosbash came to Brandeis in 1974 as an assistant professor, he became increasingly interested in a subject with far-reaching consequences: the influence of genes on behavior. Soon after his arrival, Rosbash was befriended by another new scientist on the faculty, Jeffrey Hall. Hall had trained under Seymour Benzer, an esteemed scientist at the California Institute of Technology who was the first to show that genes dictate the day-night cycle of activity in fruit flies when he identified a mutation in the Drosophila gene period. "Jeff told me about the history of the research, the people, and the science, and we decided to collaborate," Rosbash explains. "We're still at it today. The personal friendship was really the driving force behind the beginning of this work."
In 1984, Rosbash and Hall cloned the period gene. Several years later, they proposed a mechanism by which a molecular 24-hour clock might work—a transcriptional negative-feedback loop. Their model still holds up, despite discoveries of additional circadian rhythm genes, and it applies to humans as well as fruit flies. In essence, the genes that are part of this loop activate the production of key proteins until a critical activity of each accumulates and turns off transcription. Phosphorylation as well as light regulation of these key proteins is also important to the timing mechanism. Although many details remain to be worked out, "there is an emerging picture of intertwined mechanisms that regulate the levels and activity of key circadian proteins, which ebb and flow in harmony with daily light and dark cycles," Rosbash says.
Over the years, Rosbash and Hall have identified other significant circadian genes and the function of their proteins, with the goal of understanding how the various pieces of the clock fit together. Rosbash's recent studies have uncovered dual body clocks in the brain of fruit flies that independently govern bursts of morning and evening activity. The clock that initiates the morning activity, however, also helps to reset the second clock that regulates movement in the evening. They speculate that mammals, including humans, also possess similar dual circadian clocks, which likely are critical to survival. The synchrony of the dual clocks is probably important not only for maintaining a precise 24-hour cycle but also for measuring changes in day length with the seasons, Rosbash says.