To developmental neuroscientist Tzumin Lee, fruit flies are a research version of Lego. “I can combine and create with them,” he says. But Lee also sees the flies as patients, albeit tiny, red-eyed ones. “We know many diseases have a genetic component, but we can't control human genotypes,” he explains. “With flies, we can create the patients we want and then learn from them.”
Like many Taiwanese children, Lee had his career plans shaped by family, and his family expected him to be a physician. But he yearned to do research.
Graduating first in his class in medical school, Lee thought that specializing in obstetrics and gynecology might allow him to do research in developmental biology. “I was so naïve,” he says. “I later realized that OB/GYNs just provide care; they don't really study development.” During his residency, Lee tried to use his sparse free time to do lab research, but discovered that “to really do research, I needed a Ph.D.”
Lee's wife, Ching-Hsien (Jessica), also was a physician, but wanted to earn a doctorate as well. He credits her with changing his focus. “Everyone thought I had a great career, but I was not happy,” he explains. “My wife inspired me to understand that there were many things I could pursue in America.”
After earning his Ph.D. at Johns Hopkins University, Lee chose to study the development of the nervous system, using the fruit fly as a model. “When I started to devote myself to the nervous system, the power of fly genetics had not been well extended to the nervous system,” he says. “The tools that people had were not sophisticated, and they were used to study other tissues of the fly.”
So Lee set about creating better tools. With Liqun Luo, now an HHMI investigator, Lee developed a way to label individual neurons in living fruit flies. The technique, called mosaic analysis with a repressible cell marker, or MARCM, is used to discover the functions of genes, as well as trace the lineages of neurons and the paths of neural impulses.
“The system lets you control the genotype of a subset of flies,” Lee says. “This tool opened up the field for studying fly brain development and function . . . . It's like a powerful microscope—you can see things you haven't seen before.”
Lee and colleagues used MARCM to discover a master development gene called chinmo. This gene appears to be responsible for telling neuron progenitor cells what types of neurons to be made at particular times of development.
“Some of my fly colleagues think I'm kind of crazy about wanting to develop techniques,” he says. “But the nervous system is very complicated—with a new tool, you can learn much more. And behind every technique I develop, there is a reason. In the long term, I think we can advance the field through these mosaic technologies.”
Lee has taken MARCM further, creating twin-spot MARCM and dual-expression-control MARCM. These refinements make it easier to identify individual neurons and their origins. The new tools led to a new goal: to map every neuron in the fruit fly brain.
“With the right tools, I want to resolve the entire fly brain circuitry on the single-cell level,” he says. “Without a place like Janelia, that would be only a dream to me. Janelia is a wonderful place to do this through teamwork.”