The Gairdner Foundation announced today that Howard Hughes Medical Institute (HHMI) researchers Thomas M. Jessell and Michael Rosbash are recipients of the prestigious 2012 Canada Gairdner International Awards in recognition of their contributions to medical science.
The awards, which are presented annually, recognize scientists responsible for some of the world’s most significant medical discoveries. Jessell, who became an HHMI investigator at Columbia University in 1985, was honored for discovering basic principles of communication within the nervous system. The Foundation states that Jessell’s work has been instrumental in revealing important steps in the process that guides the early development of neurons, as they establish the precise connections between the spinal cord and muscles.
Rosbash, who became an HHMI investigator at Brandeis University in 1989, was highlighted for discoveries that have revealed the genetic underpinnings of the circadian clock. Circadian clocks are active throughout the body’s cells, where they use a common genetic mechanism to control the rhythmic activities of various tissues. Rosbash, Jeffrey C. Hall, emeritus professor of biology at Brandeis University, and Michael W. Young of the Laboratory of Genetics at The Rockefeller University, were honored by the Gairdner Foundation for pioneering discoveries concerning the biological clock responsible for circadian rhythms.
The Canada Gairdner Awards will be presented at a dinner in Toronto in October as part of the Gairdner National Program, a month-long lecture series given by Canada Gairdner Award winners at 21 universities from St John’s to Vancouver.
Thomas M. Jessell, Ph.D.
For the past two decades, Thomas Jessell has worked to understand how nerve cells in the developing spinal cord assemble into functional circuits that control sensory perception and motor actions. Ultimately, his research may provide a more thorough understanding of how the central nervous system is constructed and suggest new ways to repair diseased or damaged neurons in the human brain and spinal cord.
“There is increasingly persuasive evidence to suggest that many neurodevelopmental and psychiatric disorders—from motor neuron diseases to autism and schizophrenia—result from defects in the initial assembly of connections in the developing brain,” says Jessell. “By understanding the cellular and molecular processes that control the normal wiring pattern of these connections, we may eventually be able to design more rational and effective strategies for repairing the defects that underlie brain disorders.”
Jessell's work has revealed the details of a molecular pathway that converts naïve progenitor cells in the early neural tube into the many different classes of motor neurons and interneurons that assemble together to form functional locomotor circuits. This molecular pathway involves critical environmental signaling molecules such as Sonic hedgehog, and a delicate interplay of nuclear transcription factors that interpret Sonic hedgehog signals to generate diverse neuronal classes.
The principles that have emerged from Jessell's studies in the spinal cord have been found to apply to many other regions of the central nervous system, thus establishing a basic ground plan for brain development. His work has also defined many of the key steps that permit newly generated neurons to form selective connections with their target cells.
One potential strategy for brain repair involves the use of stem cells, and Jessell and his colleagues have demonstrated that mouse embryonic stem cells can be converted into functional motor neurons in a simple procedure that recapitulates the normal molecular program of motor neuron differentiation. Remarkably, these stem cell-derived motor neurons can integrate into the spinal cord in vivo and contribute to functional motor circuits. This work may uncover additional aspects of the basic program of motor neuron development, as well as pointing the way to new cell and drug-based therapies for motor neuron disease and spinal cord injury.
“I enjoy the search for answers to intriguing problems in biology,” explains Jessell. “On those rare occasions when a definitive answer emerges, there is great pleasure in having deciphered a small fragment of a much larger and still elusive puzzle. And when frustration comes, it is usually from a sense of impatience—the desire to know answers more rapidly than they emerge.”
Michael Rosbash, Ph.D.
Most scientists spend their careers exploring the depths of one specialized field. For more than 25 years, Michael Rosbash 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, metabolism and many 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 jet lag, insomnia as well as other sleep syndromes, and even metabolic disorders. All these processes are regulated by circadian rhythms.
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. This interest may have remained dormant without meeting another new scientist on the faculty, Jeffrey Hall. Hall had trained under the late Seymour Benzer, an esteemed scientist at the California Institute of Technology. He was the first to show that genes dictate the day-night cycle of activity in fruit flies when his laboratory 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. “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 feedback 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 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 group has also 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. Rosbash speculates that mammals possess similar dual circadian clocks. The integration of multiple clocks is probably important not only for maintaining a precise 24-hour cycle but also for adapting physiology to seasonal changes in day length, at least in animals.