When people think of neuroscience, they think of neurons, the cells that receive and transmit information throughout the brain and body.
“But that is only half the story,” Dr. Aakanksha Singhvi said.
Neurons make up only half the cells in our nervous system. The other half of our brain are cells called glia. Glia are intermixed with neurons throughout the nervous system. At every information-processing step, glia interact with and work alongside neurons to perform critical nervous system functions. Disruptions in glial cell activity can contribute to brain cancer, multiple sclerosis, autism and neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease.
Despite the importance of glia, research into how they function has been limited. Most brain researchers focus on studying neurons, partly for technical reasons and partly for familiarity. Often, glia have been dismissed as simple helper-cells whose function was well-enough understood. However, there is a growing appreciation for how important these cells are for nervous system health. Still, there are many unknowns about how they work.
This has not deterred Singhvi from trying to learn more about these important cells — she has always been driven to understand the unknown. Even from an early age, growing up in India, Singhvi recalled asking basic questions about life and health.
“I’d ask ‘Why do people get sick? How do they remember? Why does my grandma get more wrinkles as she gets older?’” she recalled. To some, these are just facts of life; for scientists, these are puzzles waiting to be solved.
Singhvi credits the start of her journey to becoming a scientist with her family’s passion for learning. Her mother was an educator, her father a physicist and her grandfather a renowned surgeon.
“My favorite part of summer vacation was hanging out in my father’s physics lab,” she remembered. That showed her the fun of basic research, and its power to address fundamental problems. While “assisting” with her grandfather’s medical practice, she met villagers who would walk days to consult him but could not afford to buy medication. This made Singhvi realize she wanted to focus her time studying something that could directly impact people’s well-being, a desire that led her to biology research.
For her Ph.D., she attended the University of California, Berkeley, where she used flies and worms called nematodes as model systems to study how neurons develop and connect in the brain.
During her Ph.D. research, Singhvi could not help but notice that, while scientists have known about the existence of glia in the nervous system for almost 200 years, for most of that time they’ve lacked the tools to really understand or investigate their function.
“How can we possibly understand the brain if we don’t know how its parts fit together?” Singhvi remembered thinking.
Having worked with worms, Singhvi realized that, with recent technological advancements, these tiny worms could be a powerful tool to investigate how glia work in the brain. The worms have neurons and, yes, glial cells, too. The specific worm Singhvi studies is special in two ways. First, its glia and neurons work much the same way as ours, using the same molecules. Second, each individual worm has exactly the same number of cells in its nervous system. This unique feature allows scientists to build precise maps that enable them to study the nematode nervous system in great detail.
"Not understanding how glia function in our brain is like reading a mystery novel with the second half missing or seeing only half of a master’s painting."
Drawn by this unsolved problem in neuroscience, Singhvi decided to join forces with Dr. Shai Shaham at The Rockefeller University in New York City. In her postdoctoral research, Singhvi discovered new mechanisms by which glia influence neuron function. Her work identified, with remarkable precision, molecules with which glia control sensory perception and memory. Such molecular detail is critical for understanding neurological diseases like autism and epilepsy.
“Fred Hutch values intellectual creativity and interdisciplinary crosstalk. Being in this enriching environment gives me the confidence to build a research program that lets me take my best shot at tackling challenging problems,” Singhvi said.
Her lab in the Basic Sciences Division is currently exploring many aspects of glial function, including the roles glia may play in aging, autism, neurodegeneration, sensation and animal behaviors.
An exciting new area of research in her lab looks at what’s called glial pruning of neuronal endings. This pruning process helps regulate how neurons connect with each other. Singhvi’s group recently discovered that worm glia also “prune” neurons.
“Glia snip away bits and pieces of neurons in a controlled manner. Think of it as the glia sculpting neurons for precise brain circuits,” Singhvi explained.
Imbalance in glial pruning can have severe consequences: too little pruning could contribute to epilepsy, too much could lead to schizophrenia, dementia or neurodegeneration.
What controls pruning, though, remains largely a mystery. Singhvi’s team is now working to understand this process better.
When asked what makes her most excited to be doing her work, Singhvi said, “New data. Somebody comes into my office and says, ‘Hey, do you want to see something interesting?’ That is the best thrill ever! I will drop everything for that. And if it’s not something we expected, that’s even more exciting!”
She credits the talent and enthusiasm of her research team for the exciting progress they are making in uncovering the role of the mysterious glia. Even so, it is clear that the field has only scratched the surface of understanding how glia affect nervous system function. “There are so many fascinating puzzles to solve around glia, and we are just getting started!” she said.
— By Matthew Ross, Aug. 6, 2020