Neural stem cells give rise to all the cells needed to build a nervous system. But how do these stem cells decide whether to become neurons, the cells that relay information from the brain to the rest of the body and back again, or glia, the cells that both insulate and support neurons? Answering that question has been a major focus of David J. Anderson's research. The outcome may one day provide the key to using stem cells for the regeneration of brain or spinal tissue that has been damaged by trauma or disease, including Parkinson's and Huntington's.
By isolating and studying neural stem cells in petri dishes, Anderson has discovered several molecules that act from outside stem cells, driving them to develop into neurons, glial cells, or even smooth muscle cells. He and his colleagues have also identified "master" genes that act inside stem cells to control their fate. Thus, expression of genes such as Mash1 or the Neurogenins in stem cells pushes them to develop into various subtypes of neurons, while expression of genes from the Olig family coaxes stem cells to become oligodendrocytes, a type of glial cell that insulates nerve fibers rather than astrocytes, another type of glial cell. Olig genes also play a role in the development of motor neurons.
"By understanding how neural stem cells choose among their various options in the laboratory, we hope to uncover important clues about how these cells differentiate in the body," Anderson explained. "This information is crucial to being able to use stem cells therapeutically."
In recent years, Anderson also has turned his attention to deciphering the neural circuits that underlie fear, anxiety, pain, and other instinctive behaviors. Disruptions in neural circuits are known to underlie psychiatric disorders like anxiety and depression. "Elucidating these neural circuits is an important first step to understanding how genes, drugs, and experience act on and modify these circuits, in both normal behavior and in disorders such as anxiety and depression. Our hope is that this work will eventually improve the diagnosis of these conditions and lead to new, improved treatments," Anderson said.
Using mice as a model system, Anderson has identified innately aversive stimuli, such as ultrasonic tones that mimic alarm vocalizations, which cause the animals to exhibit a characteristic freezing response or to flee, depending on their ambient level of stress or anxiety. He is also working to map the neural circuits that are activated during these behaviors and to identify the genes that control the freezing and flight responses. Anderson is also conducting parallel studies in the fruit fly Drosophila, which appears to emit an odor when stressed that causes avoidance by other flies. The ultimate aim is to understand how, where, and when genes act to direct the function of these neural circuits, and thereby affect behavior.
Anderson credits his postdoctoral advisor and career mentor, Richard Axel, a fellow HHMI investigator and winner of the 2004 Nobel Prize in Physiology or Medicine, for influencing his approach to scientific problems. It was during a fellowship in Axel's Columbia University laboratory in the early 1980s that Anderson became intrigued by the developing nervous system and set out to apply molecular biological techniques to understand how different cell types are specified and determined during development. To this day, the two investigators continue an active collaboration.
"Richard has the uncanny ability to find the soft underbelly of what otherwise looks like an armadillo of a problem—impenetrable—and to get into it and get a tremendous amount of traction on the problem," Anderson said. "I wouldn't say that I have come close to his ability to do that; I'm not even sure it is something that can be learned. But I certainly know it when I see it, and I saw it in action from Richard and learned the importance, at least, of thinking in those terms."