People who knew Chris Doe as a child didn’t need a medium or a crystal ball to know he was likely to pursue science of some sort. A Jacques Cousteau devotee, Doe built makeshift submarines in his Southern California backyard and tried them out in various lakes and streams.
“My path was easily predicted early on,” Doe laughs. What wasn’t so obvious was how a passion for oceanography resulted in a life’s work studying neural stem cells and neural development.
As a biology major at the New College of Florida, Sarasota, Doe met his first mentor, John Morrill, a developmental biologist working on sea urchins. Peering through the microscope in Morrill’s lab, Doe watched an organism develop from a fertilized egg.
“I got really excited about developmental biology in college and that was where I switched from wanting to be an oceanographer,” he says. It was with that excitement that Doe entered Stanford University as a graduate student to study how stem cells from grasshoppers develop into neurons. "The inspiration was similar to early development: how does a single stem cell generate so many different types of neurons?" says Doe, “but when I went to Stanford I didn’t know much about how to answer these questions using molecular biology or genetics.”
That changed when he took a class from fruit fly geneticist David Hogness. “That class was a turning point in my career. I just thought, what am I doing working with grasshoppers? You can make mutants and get molecular mechanisms from Drosophila [fruit flies].”
As a postdoctoral fellow in HHMI investigator Matthew Scott’s University of Colorado lab (Scott now directs a lab at Stanford University), Doe discovered his first intriguing Drosophila mutant. The mutant has a defect in a gene that regulates other genes. As a result, it triggers nervous system cells to change their identities. Doe dubbed the gene Prospero.
“We took the name from the magician in Shakespeare’s The Tempest,” he says. “We and others have since discovered proteins that bind to Prospero and have named them Miranda and Caliban after other Tempest characters.”
The work on Prospero has led the Doe lab to study how neural stem cells are maintained. Mutants such as prospero and miranda lead to brain tumors due to the transformation of neurons back to neural stem cells. Other mutations have the opposite effect of eliminating neural stem cells, producing flies with extremely small brains. Doe says that these genes may be used to change brain size in other insects, such as honeybees, which have a larger brain than fruit flies. “We can now ask questions about how social insects with complex behaviors, like honeybees and grasshoppers, have evolved bigger brains,” Doe notes. “And we will be looking to see if these genes are expressed in mouse brains.”
As fascinating as the brain evolution work is, Doe’s lab is increasingly dedicated to understanding how a neuron knows with which neurons to form circuits. “If we are ever going to be putting stem cells back into the brains of patients, we need to understand how a neuron knows it is hooking up with the right circuit,” Doe says. “What is in the developmental history of a neuron that allows it to join with the proper circuit? Nobody has a model for how that happens.”
Doe’s group is approaching this question from two directions. In collaboration with Janelia Farm group leader and computational biologist Eugene Myers, they are attempting to make a 3-D atlas of the neurons in the fruit fly central nervous system. "Once we have learned where every neuron is positioned, we can map which genes are on or off in each neuron, which will give us a 'name and address' for each neuron," Doe says.
The next step is to decipher which neurons are talking to each other as the newly hatched fly larva crawls, turns, or reverses direction—the easiest behaviors to analyze. To do this, the Doe lab is teaming up with University of Oregon neuroscientist Shawn Lockery, who has developed methods to simultaneously record the activity of single neurons and larval behavior. Doe explains, "We make a transgenic fly where each neuron emits a pulse of green light when it is active and watch them 'talking' as we record the behavior of the larvae."
In this way, the group hopes to map out the network of neurons that control different aspects of behavior, an important goal in neuroscience. "The combination of mapping active neurons, and having the 'names and addresses' of each neuron from our atlas should be an incredibly powerful tool to monitor and manipulate single neurons," says Doe.
A longer term goal is to map out the gene expression patterns shared by neurons in a circuit. “This will help us determine what neurons in a particular circuit have in common,” Doe says. “This is probably a 10-year project. But I think it is the best way we can get clarity about why neuronal circuits are forming the way they do."