A little circuitous is how Gail Mandel describes her route to becoming a neuroscientist. She started off in graduate school in immunology but enjoyed being a postdoctoral fellow so much she did three: in the biochemistry of membranes, in bacterial genetics, and in the molecular biology of the polyomavirus.
It was at her first faculty position at Tufts New England Medical Center in the mid-1980s that she became interested in neuroscience. She wanted to apply her newly obtained experience in molecular biology to an important topic, understanding how the brain works. This was before the modern field of molecular neurobiology existed. She started out working on one protein, which led to another very interesting protein called REST. Her REST research has shed light on how the nervous system develops and how neurons maintain their integrity. Besides increasing understanding of the nervous system, her investigations with REST have implications for research about development, gene expression, stem cells, and disorders such as autism.
Before finding REST in 1989, her goal was to clone the voltage-dependent sodium ion channel because it is a key membrane protein involved in all electrical communication in the brain. "There was painfully little information to go on," Mandel says. But the late biochemist Shosaku Numa had provided the first DNA sequence of the sodium ion channel from the electric eel.
Mandel set out to clone the mammalian counterpart of the sodium channel in skeletal muscle, and she did. "The successful identification of the gene provided a valuable reagent that unlocked the basis for diseases, including one that causes paralysis in race horses due to mutations in the gene," Mandel says. "But the biggest boon of cloning the sodium channel was seeing how its structure related to its function."
Mandel was less interested in the physical organization of the channel, as other scientists were. "Trained in gene regulation during my postdoc, I wanted to exploit the universality of sodium channels in neurons to see what turned the gene on in the mammalian nervous system," she says. "I reasoned that, because the sodium channel gene is so important to the nervous system, understanding how a cell chooses to express the right channel gene might give insights into what makes a neuron different from other types of cells." Although each cell in a tissue—such as lung, liver, or kidney—contains the entire genome, each expresses only those genes it needs to maintain its unique identity.
On her quest to understand what controls gene expression of the sodium channel in neurons, Mandel expected to find a protein that activates the gene. Findings from liver cells had suggested that positive stimulation of liver cell genes maintains their cellular distinctiveness. "Instead, I found nervous system gene expression is sustained in a completely surprising way," she says.
She showed that neuronal identity in the adult nerve cell is defined not by an activator, but by the absence of an inhibitor protein, which she found in 1995 and called REST. When REST is absent in neuronal cells, neuronal genes are expressed. REST's presence in nonneuronal cells represses neuronal genes. Current genome-wide techniques reveal that REST silences 8,000 neuronal genes in nonneuronal cells, making it a master regulator of neuronal identity.
Mandel also has shown REST's importance during nervous system development, when stem cells differentiate into the various cells that ultimately make up the nerves, spinal cord, and brain. REST is present in cells slated to become neurons, yet it keeps neuron genes turned off. At some point REST disappears when the cell matures and neuron genes are expressed.
"REST keeps DNA looser in developing neuronal cells than in nonneuronal cells, where REST acts on DNA like a clamp, like a much stricter parent," she says. Mandel is studying REST repression mechanisms and how REST vanishes at the right time in development to allow nerve cells to form and express their genes. Her research should help efforts to reprogram mature cells into stem cells or other cell types. Reprogramming could someday allow the recapitulation of disease processes from patients' tissue or the creation of new tissues, such as insulin-producing cells from the pancreas.
Mandel additionally studies the relationship between REST and Rett syndrome, an autistic disorder that strikes girls. But unlike other Rett syndrome scientists who focus on the neuron, Mandel studies glial cells, cells that support neurons. "Our perspective is different," she says. "As a result, we hope to make a different contribution."
Mandel has enjoyed and continues to relish taking the road less traveled in her career. Recently, she left a position where she had been for 20 years, uprooting herself physically and intellectually. She is now at the Vollum Institute, a basic science facility at Oregon Health & Science University. "For me, it was a chance to talk to physiologists and other scientists here, think about higher brain function, and do things that are different," she says. "I always like new approaches and challenges."
