Developmental Biology, Genetics
The University of Texas Southwestern Medical Center
Dr. Pan is also the Fouad A. and Val Imm Bashour Distinguished Chair in Physiology at the University of Texas Southwestern Medical Center.
Control of Organ Size and Tumorigenesis by the Hippo Signaling Pathway
Duojia Pan grew up in China in the 1970s as the country was pushing for modernization. "My parents—and I think many Chinese parents—wanted their children to grow up to be scientists," says Pan. Looking back now, he thinks he was lucky because that "social epidemic" coincided with his own desire to become a scientist.
With each step in his education, he stayed focused on his goal, applying in college to an elite program called CUSBEA (China-United States Biochemistry and Molecular Biology Examination and Administration) that helped Chinese biology students come to the United States for graduate school. Pan and some 50 other students were chosen to spend a preparatory year in China, taking intensive English classes and learning to navigate American society, including such skills as how to open a bank account and write a check. When he arrived at the University of California, Los Angeles in 1989, that preparation allowed him to focus on his research and course work.
Now a molecular biologist at the Johns Hopkins University, he has continued his methodical approach to science, moving one small step at a time to answer a big question. That trajectory included a postdoctoral fellowship in the UC Berkeley lab of Gerry Rubin, now HHMI vice president and director of the Janelia Farm Research Campus.
Along the way, Pan's big questions have involved how organs know to grow to a prespecified size and shape. Biologists have identified many of the signals that tell a cell what type of cell to become and where to go within an organ, but they know much less about the signals that control the size of the organ. It is like asking a cell in the middle of a wing to know how big the wing is, Pan says. Rather than tackling that overarching abstract question, Pan has broken it down into smaller, more tractable questions. Initially he looked for mutations in Drosophila that caused a group of cells to grow beyond the number they would in a normal, or wild-type, fly.
Pan's team identified a gene, hippo (abbreviated as hpo), that when mutated in a developing fly leads to an abnormally large eye. The researchers found that hpo lies in the middle of a signaling cascade, and they have pieced together each step that occurs after hpo is turned on. During normal development, hpo passes a "stop growing" message down the pathway through several other proteins, which induce expression of genes that limit cell division and promote cell death.
The part of what Pan calls the Hippo pathway that comes before hpo remains an enigma, and that is where he thinks the key to size control lies. Pan can describe several models of how such a system might work. For example, each cell in an organ may secrete a particular protein. As the number of cells increases, the concentration of that protein would increase as well, eventually reaching some threshold at which it turns on the Hippo pathway. But rather than spending a lot of time discussing what could be happening, Pan prefers to talk about what his group is doing to systematically look for the key signals.
In one approach, the group is using a technique called RNA interference (RNAi) to turn off each gene in the Drosophila genome, one at a time, in tissue culture cells. The researchers use a high-throughput screening system to determine whether the Hippo pathway is active in the absence of a given gene. To complement this approach, Pan is also using a system, called a two-hybrid screen, to look for proteins that bind directly to the Hpo protein. In this case, Hpo is bait, just like a worm on a hook used to lure a fish from a pond.
In 2007, Pan and his colleagues showed that shutting off the Hippo pathway in the livers of mice caused the organ to grow to five times its normal size, eventually leading to cancer. That experiment showed that hpo function is conserved in mammals. Pan's team plans to engineer other transgenic mice in which the Hippo pathway is disrupted in other organs and at different times during development to find out if it is generally used to control the size of different organs.
Finding that key to organ size is the Holy Grail, Pan says. And he says he has experienced immense satisfaction on the way to that goal, although he spends more time thinking about what to do next than about what he's already done. He acknowledges that the social pressure to focus on science wouldn't be ideal for every child but that it worked out well for him. "I had this dream and ambition very early on, from elementary school. So it was always about taking one step closer to where I am now and where I am going next. I had this ambition to become a scientist since childhood. What a fortune it is to realize that dream."