Cancer Biology, Cell Biology
The University of North Carolina at Chapel Hill
Dr. Bear is also an associate professor of cell and developmental biology and a member of the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill School of Medicine.
James Bear was sitting in 10th grade AP Biology at Skyline High School in Salt Lake City when the realization hit him. "Hey, I could do this: biology could be my career, and I want it to be. It just clicked."
Still, Bear saw college as his "last chance" to take a wide variety of courses, so he chose a small liberal arts school: Davidson College. There, he became interested in developmental biology and moved on to Emory University for a Ph.D., studying an unusual forest-dwelling amoeba called Dictyostelium, or slime mold.
These organisms exist as individual amoebae when food is plentiful. But when food becomes scarce, they join forces. Tens of thousands of amoebae cluster together into what looks like a blob of petroleum jelly. This cluster develops into a pouch full of sporescalled the fruiting bodythat can be dispersed to more nutrient-rich environments.
Bear focused on a gene called cAR2 and its role in Dictyostelium development. Without cAR2, slime mold cells arrest about halfway through formation of the fruiting body. Bear identified a slime mold strain that could bypass this block and complete development even in the absence of cAR2. This strain, Bear discovered, lacked a gene he named SCAR, for "suppressor of cAR2."
It turns out that homologs of SCAR (also known as WAVE) are present in many other organisms, including humans, and are essential to cell movement. That discovery set Bear on a path to understand how different kinds of cells move.
Single-celled organisms, like amoebae, move from place to place. Cells in more complex organisms are constantly in motion, too. Individual cells move as they divide, muscle cells move when they contract, and, during development, cells move from one part of the body to another. All these movements involve changes in the cell's inner structure, or cytoskeleton. Composed of microtubules and actin filaments, the cytoskeleton gives a cell shape and allows it to move, grow, and divide. A cell remodels its actin infrastructure almost constantly, creating protrusions used for cell movement.
Bear found that slime mold cells lacking SCAR have fewer actin filaments. Other researchers later discovered that the protein encoded by SCAR is one of the main activators of a protein complex called ARP2/3. The complex binds to actin filaments and causes new filaments to sprout at the leading edge of a moving cell.
Having developed an interest in the cytoskeleton and cell movement, Bear secured a postdoc at the Massachusetts Institute of Technology in the lab of Frank Gertler, where he began studying the Ena/VASP proteins—a family of proteins that help actin filaments grow. Many researchers thought that Ena/VASP proteins would help cells move faster, but Bear found the opposite to be true. Working with mammalian cells, he discovered that when cells produced high amounts of Ena/VASP, they moved slowly; when the proteins were removed, the cells crawled faster. "That was very surprising to us," Bear says.
Bear later worked out the reason for the discrepancy. Ena/VASP proteins interfere with the function of other proteins that normally cap the ends of actin filaments. This capping leads to short filaments and more branching, which stabilizes protrusions and leads to faster movement. When Ena/VASP is present, actin filaments grow longer and have few branches. With less stable protrusions, the cell moves more slowly.
After establishing his own lab at the University of North Carolina at Chapel Hill, Bear began investigating coronins, a family of proteins known to be involved in cell movement. "I decided to take a risk and study something related and important, but that was not well understood yet," he explains. But he soon found out that breaking new ground as a beginning investigator has its challenges. "I'd never published on coronins before and nobody knew what they did," he says. "My first couple of grants were excoriated. 'Very promising investigator... Clearly doesn't know what he's doing.' "
Despite the discouraging initial reviews, Bear stuck with his plan. "In my heart, I knew I was doing what I wanted to do, and that there would be interesting results." He was, and there were. Bear discovered that coronins drive cell movement in multiple ways. They inhibit ARP2/3—the same complex that SCAR turns on. They also help coordinate the turnover of actin filaments.
Bear has also begun to explore coronins' role in human disease. Cell movement isn't always good—cancer cells use it to metastasize. Bear has discovered that high levels of the coronin 1C protein exist in advanced melanoma, a deadly form of skin cancer. He is now investigating whether the protein could serve as a marker for predicting which tumors might spread.
Though Bear says he'll probably always take risks, his experience has brought perspective. "I think taking risks is an important characteristic of anyone who's successful," he says. "But I'm learning to balance that with being more cautious and, hopefully, a bit wiser."