Janelia Research Campus
Dr. Baker is a group leader at the Janelia Research Campus.
Genetic Specification of Neural Circuitry for Innate Behaviors
The best scientists, Bruce Baker believes, are those who persevere with the problem they're trying to solve, even if they must leave their comfort zones. "If they're geneticists, and they reach a point where molecular biology is needed, they have to learn molecular biology and keep pushing," says Baker, who followed in his father's footsteps when he became a geneticist. In the 1980s, he took his own advice by branching into molecular biology to further his studies of genes and sex.
When Baker began his research, he spent his time crossing fruit flies, as geneticists had done since 1910. But it then became possible to chemically mutate fruit fly genes and study the effects. "This clearly offered the potential to ask a whole array of questions that had never been conceived of previously about how genes function to build an organism," Baker says.
It was known that certain genes make fruit flies male or female. But until Baker set up his lab, no one had asked how those genes guide sexual development. "I could see a set of developmental questions that would let me address sex determination and move into developmental biology, which was just beginning to become an exciting field," he recalls.
By 1980, his group had discovered a cascade of genes that determines how tissues and organs develop in sex-specific ways. In this bureaucratic chain of command, each gene tells the next one how and when to act.
A gene called doublesex, which controls features such as pigmentation and genital anatomy, is the last one in the cascade, Baker discovered. In the 1980s, he suggested that this master switch might function one way to create female sex organs and another to make male ones. The idea that a gene can have two active states rather than being just on or off was radical at that time, because the first example in cells had been found only in 1980.
To test his idea, Baker had to clone the gene and see if it could be copied, in more than one way. Because he lacked the necessary skills, he hired a molecular biologist as a postdoc, and the two worked side by side at the bench for months. After they cloned the gene, they showed that it does in fact lead a double life. This is possible because transcripts of the gene are edited differently in males and females, resulting in different, but related, proteins. Other genes in the cascade can also be edited two ways.
With collaborators in Texas, Massachusetts, and Oregon, the group made another surprising finding. They initially thought that doublesex was responsible for all the differences between male and female flies, including courtship behavior. So they were shocked to discover that male flies without the gene can tap female flies with their forelegs, sing songs with their wings, lick females' genitalia, and copulate with the same panache as normal males. Therefore, they had to look elsewhere for the courtship gene.
Using a clever molecular screen, postdoc Lisa Ryner identified a gene that shares an important feature with doublesex. Looking for information about this obscure gene, Baker and his collaborators found that males with certain versions of this gene court males as well as females. And their work showed that males harboring other versions of the gene were also inept suitors. "That was exactly what we thought we should be finding," he says. "It was very much like going to Las Vegas and hitting the jackpot."
The group showed that this fruitless gene is part of the sex determination cascade but sits on a different branch than doublesex. "If evolution has seen fit to dedicate groups of genes to build each physical part of the body, it seems logical that it would also dedicate groups of genes to building the circuitry in the nervous system that is responsible for innate behaviors," Baker says. "And courtship, which leads to reproduction, is about as important a behavior as you can have."
Fruitless is expressed mainly in the central nervous system, where it becomes active in 2 percent of the cells 2 days after larvae pupate. Baker finds its role in nervous system development both "provocative and pleasing." It is pleasing that a gene can control courtship singlehandedly, and provocative that genes might affect human encounters with the opposite sex. But extrapolation is unwise, Baker warns. The human genome contains about 60 relatives of fruitless, but none are yet tied to behavior. However, it also contains doublesex and several other genes in the cascade.
At Janelia, Baker hopes to understand how fruitless directs the formation of the neural circuitry responsible for male courtship behavior. And he will try to determine how that circuitry responds to sensory clues to elicit such complex behavior. His motivation to prolong his career beyond 35 years is not to earn more accolades but to satisfy an internal need. "To me research as a process is much like how I imagine an artist approaches and creates a work of art: by bringing vision to reality [and savoring] the pleasure of creation," he explains.