Michelle Gray says her mother knew never to tell her a story unless she could account for every detail. “If you told me one sentence, I was going to ask you another question,” Gray says. “I was always in pursuit of more knowledge.”
Gray grew up in Alabama and attended Alabama State University, earning her bachelor’s degree in biology in 1997. She then headed to Ohio State University for her PhD and chose to work alongside neurobiologist Christine Beattie on the startle response of zebrafish. Gray and Beattie’s experiments showed that the neural circuits involved in the response are malleable, which might have been essential in the evolution of predator avoidance.
Having studied the development of neurons, Gray realized that she wanted to apply her knowledge to study the other end of the cell cycle: neurodegeneration. The topic was quite a...
One of the researchers she contacted was neuroscientist X. William Yang. He had just started his own lab at the University of California, Los Angeles, after helping to pioneer the development of the bacterial artificial chromosome (BAC), a molecular tool used to clone chunks of DNA up to 300,000 base pairs long. Yang planned to use BACs to create transgenic mice for the study of neurodegeneration in Huntington’s disease, a fatal brain disorder. He agreed to take Gray on as a postdoc to help develop the Huntington’s mouse model. “I give her a lot of credit . . . for being very bold,” Yang says. “I was proposing to do things that hadn’t actually been done before.”
Huntington’s disease is caused by a dominant mutation in the huntingtin gene. Together, Yang and Gray created a mouse model, called BACHD, which included the full-length mutant human huntingtin gene along with a molecular switch to reduce the expression of the gene in individual cell types. That was important because no one knew which cells were most important to the disease, Gray says.
After the model was made, it fell to Gray to characterize BACHD by detailing the behavioral, cognitive, and muscular changes the mice experience when expressing the human form of huntingtin. Because it takes more than a year for the animals to show a full suite of symptoms, the work could be frustratingly slow, she says, but her diligence paid off: BACHD mice are now widely used in Huntington’s disease research.
“For cell type–specific effects, the BACHD is really the best model out there,” Mahmoud Pouladi, a neurogeneticist at the National University of Singapore, tells The Scientist. Pouladi uses BACHD to study the disease’s effect on neuronal support cells called oligodendrocytes. When it comes to the types of questions this model can answer, Pouladi says, “the limitation is only our imagination.”
Using the model, Gray and her colleagues showed that reducing huntingtin expression in cortical neurons led to a partial improvement in the animals’ motor and behavioral deficits. Reducing gene expression in both the cortex and the striatum, however, provided even more dramatic results; it led to a reversal of every symptom afflicting the diseased mice, prevented brain atrophy, and bolstered the repair of neuronal connections linking the two brain regions. The results, Yang says, informed current efforts to develop treatments for Huntington’s disease, including a drug now in a Phase 3 clinical trial that reduces levels of the mutant protein.
After wrapping up her postdoc, Gray started her own lab at the University of Alabama at Birmingham in 2008. There, she decided, she’d study the role of neuronal support cells called astrocytes in Huntington’s. When Gray first mentioned the line of research to Yang, he says he remembers thinking it was risky, “because at the time very few people thought astrocytes could be important.”
Taking the risk paid off. Gray and other biologists at the university’s Center for Glial Biology in Medicine showed that BACHD mice with reduced human huntingtin expression in their astrocytes don’t decline as quickly as BACHD mice with normal expression levels, suggesting that astrocytes play some role in the disease’s progression. Through her work with the Huntington’s Disease Society of America, Gray has witnessed that progression in human patients, she says. That’s when “you fully appreciate that [your research] is really going to be instrumental in people’s lives.”