Biochemistry, Molecular Biology
University of Pennsylvania
Dr. Dreyfuss is also Isaac Norris Professor of Biochemistry and Biophysics at the Perelman School of Medicine at the University of Pennsylvania.
Gideon Dreyfuss is interested in RNA-binding proteins and their complexes with RNAs (RNPs), the key mediators of post-transcriptional gene regulation, and their role in disease. His current research focuses on the SMN complex, an RNP assembly machine; spinal muscular atrophy, the motor neuron degenerative disease caused by SMN deficiency; splicing regulation; and high-throughput technologies for research and drug discovery.
It's hard to escape family tradition. With three generations of physicians before him and his two brothers having chosen the profession, Gideon Dreyfuss seemed to have made a break by becoming a scientist. "I was incredibly fascinated by and attracted to hard sciences," says Dreyfuss, who studied chemistry and physics at university in Jerusalem, before pursuing a Ph.D. in protein biochemistry at Harvard University.
In his postdoc years, Dreyfuss became interested in what he calls the "life story" of RNA and how proteins interact with RNA in cells, enabling it to perform its function, transcribing the instructions encoded in DNA and translating them into proteins. When strands of RNA are first transcribed from DNA in the cell's nucleus, they are referred to as pre-messenger RNAs (pre-mRNAs). They are then cut up and rejoined, splicing out introns and connecting exons, to produce mature messenger RNA (mRNA). These processes are orchestrated, Dreyfuss discovered, by proteins bound to RNA in cells.
A major challenge in finding RNA-binding proteins is that associations between proteins and RNA molecules are lost or rearranged when cells are broken apart and studied. One of the first experiments Dreyfuss conducted as an independent researcher at Northwestern University was to shine ultraviolet light on living cells to cross-link, or "glue," proteins and RNA together, thereby capturing genuine RNA-protein interactions that occur in cells. "When I first proposed the experiment it was criticized as not realistic, but in a very short time we demonstrated it was working," he says.
Using this novel approach, Dreyfuss identified the very first definitive group of RNA-binding proteins in 1984. In subsequent years, his group found additional proteins bound both to pre-mRNA and mRNA, and with them the group was able to build a picture of the roles these molecules play in the formation and function of mRNA. The experimental approaches, reagents, consensus motifs, and other insights that emerged from these studies facilitated the discovery of numerous RNA-binding proteins and led to a wide appreciation of their roles in gene expression.
His lab also discovered that whereas some RNA-binding proteins are confined to the nucleus, others shuttle between the nucleus and the cytoplasm. These shuttling proteins have a role in transporting mRNA from the nucleus to the cytoplasm, where it can be translated into proteins. Over several years, Dreyfuss and colleagues determined the amino acid sequences that serve as "signals" for the localization and transport of proteins and identified the cellular machineries involved in process.
But medicine, the family tradition, crept back into Dreyfuss's research. In 1995 a French group discovered that a disease called spinal muscular atrophy is caused by mutations in a gene called survival of motor neuron (SMN). Dreyfuss had identified the SMN protein a short time earlier, as a protein that forms a complex with several RNA-binding proteins. He subsequently determined that the SMN complex is necessary for assembling small ribonucleoproteins—the building blocks of the cell's splicing apparatus. "The function of SMN in ribonucleoprotein biogenesis [the assembly of RNAs with their RNA-binding proteins] was completely unanticipated because it was widely believed that this process occurs in cells spontaneously by self-assembly," says Dreyfuss. "Just as unexpected was the discovery of the role of SMN in splicing."
The finding provided the first insight that spinal muscular atrophy may be caused by splicing errors. In a 2008 study, Dreyfuss determined that mice deficient in SMN—an animal model for the most severe forms of the human disease spinal muscular atrophy (SMA)—exhibit reduced amounts of different types of small ribonucleoproteins in different cells. These variations lead to widespread pre-mRNA–splicing defects in diverse genes.
Dreyfuss reasoned that one approach to treat the disease would be to restore normal levels of SMN activity. But drug companies were not willing to take on this task. "Most pharmaceutical companies are interested in finding cures for more common diseases," says Dreyfuss. "Having met patients with this disease, this was upsetting to me. I thought there were potential therapeutic approaches coming from our own work."
With support from the AFM (Association Française contre les Myopathies), Dreyfuss set up the necessary apparatus in his lab to screen thousands of compounds to identify ones that would increase SMN activity in SMN-deficient SMA patient cells. Once he showed the feasibility of the approach, Dreyfuss was able to interest the pharmaceutical giant Merck in helping him carry out a much larger screen. "You have a better chance to find drugs with a larger library of compounds, and the largest ones are only available at a few large pharmaceutical companies," he explains.
The versatile technologies he developed for these high throughput screens may also lead to therapies for other diseases. Dreyfuss and his colleagues recently discovered that the SMN complex may play a role in diseases caused by oxidative stress, such as Alzheimer's and Parkinson's disease.
Today a major focus of the Dreyfuss lab is searching for potential medicines, bringing his work closer to his family profession. "When the connection between SMN and disease came along, it was my fate to go after it," he says, laughing.