As reported by The Hartford Courant, November 15, 2005.

Divide and Conquer

UConn, Yale Scientists Dig Into Functions Of Cell's Molecules

By William Hathaway

Within a cell invisible to the naked eye, researchers at the University of Connecticut Health Center plan to erect a tiny fence of proteins using chemicals activated by light so they can better study the workings of the basic unit of biology.

Other UConn researchers backed by $12.3 million in grants that the National Institutes of Health awarded to UConn and Yale in October have devised computer software that tracks interactions of millions of molecules within a cell and will conduct "virtual experiments" on their function.

The grant, one of the largest ever awarded to the health center, will finance the work of 17 researchers at UConn and Yale University who are developing tools to help answer questions about fundamental cellular processes that misfire in many diseases.

"The ironic thing is that we can't possibly understand life working only with our own brains. We need a computer and other technological tools to keep track of the information that our brains collect," said Dr. Leslie Loew, professor of cell biology at UConn and principal investigator for the grant.

In the late 1990s, Loew began work on software that would create a "virtual cell" -essentially an electronic catalog and map of the many different kinds of molecules that make up a cell. The work evolved seven years later into the NIH grant to help design technology that scientists need to harness the wealth of information that has followed the mapping of human and animal genomes.

At the end of the 20th century, much of the scientific world was transfixed on scientists' efforts to decode DNA, or the sequence of a few billion letters of genetic information tucked inside the nucleus of every cell.

The sequencing of the genome was a remarkable achievement but "was only the beginning" in understanding how cells function, Loew said.

DNA contains the instructions for making, say, an eye, but decoding the DNA did not reveal why some cells become part of the retina or how they end up in the right place or what happens to make a cell in the eye function differently than a bicep muscle.

Since then, scientists have learned much about the importance of gene expression - when and in what order the genes are activated in a cell. Scientists also launched investigations of the interactions of proteins - the products of genes that govern much of life's functions.

Researchers now realize that the location of proteins and small molecules within cells helps regulate the cells' ability to receive and transmit information that determines their function. However, many details of cell signaling remain a mystery.

The NIH grant to UConn and Yale is one of five awarded to academic institutions and researchers in a variety of different disciplines around the country that dig into details of unanswered biological questions.

"The piece we need to define now is who talks to whom," said Ann Cowan, deputy director of UConn's Center for Cell Analysis and Modeling. "We need to find the dancing partners in the cell and find out where the dance takes place."

One way to determine the interactions between myriad proteins and molecules within the cell is to keep the dancing partners apart and watch what happens.

Paul Campagnola, assistant professor of cell biology at the health center, uses light to create a barrier within a cell. A chemical agent injected into the cell is activated by light focused at a precise location. The resulting reaction between light and the chemical binds proteins together, creating a tiny protein barrier at the targeted area within the cell.

Using the technology, scientists can create minuscule compartments within cells. The barriers will help scientists determine which areas of the cell are most important in cell signaling.

For instance, Vladimir Rodionov, associate professor of cell biology at the health center, is interested in the role of microtubules - filaments within a cell that act as a conduit for nutrients and other molecules. Rodionov wants to see whether creating a molecular fence that blocks the microtubules will affect how a cell moves, migrates and interacts with neighboring cells.

At Yale, Eric Dufresne, assistant professor of mechanical engineering, chemical engineering and physics, uses a tool called a holographic optical tweezer to move proteins around on the surface of a cell in groups. Many proteins can be attached to tiny glass beads and manipulated simultaneously using only focused light beams, he said.

Such tools are designed primarily for research, and most have no immediate clinical applications, scientists say. But Rodionov points out that understanding cell migration, for instance, is crucial to understanding many disease processes, such as cancer metastasis.

"That is the adventure of cell biology," Radionov said. "It will lead us, well, I don't know where."