Emory Report

September 13, 1999

 Volume 52, No. 4

Vicky Finnerty searches for a new cancer pathway

More than 1,500 people in the United States will die from cancer each day; that's equivalent to a daily sinking of the Titanic.

This tragedy continues, in part, because cancer is perhaps the most complicated of human afflictions; curing cancer is analogous to automotive repair by a mechanic with almost no understanding of how a car functions and working blindfolded. Peeking under that blindfold is biology Professor Vicky Finnerty, who hopes to further understanding of the mutated colorectal cancer (MCC) gene.

Scientists originally discovered the MCC gene by following genes with correlations to colorectal cancer. The gene itself was named MCC after the cancerous condition to which it was thought to be related, but later research focused on a more promising gene candidate. However some researchers, like Finnerty, feel the issue was dropped too quickly.

"I think we need to understand every gene that is even remotely involved in cancer," Finnerty said. She has focused on the fruit fly form, or homologue, of the human MCC gene; almost one-third of the human genes now known to be involved in cancer were originally discovered by studying cell signaling in flies.

"The bottom line is that [human and fruit fly] genes are not only homologous in their DNA sequences, but the proteins these genes encode have functional similarity," Finnerty said. "The function is not always the same in all organisms, obviously, but it would be like thinking about a song-that song is played throughout many different species, but the lyrics are a little different in different organisms."

So far Finnerty has found that briefly turning off the gene leads to flies with crumpled wings, misdeveloped legs and tumors. She turns off the gene by injecting flies with a gene producing antisense RNA. During normal development, DNA sequence is transcribed as RNA, which then becomes the template for a protein. But a reverse sequence of the RNA (antisense) will attract and bind the normal RNA sequence, much the same as two opposite magnets. Since the RNA is now locked up, it cannot be used to make protein.

In this situation, the RNA is only being bound when the antisense gene is "turned on" and producing antisense RNA. All genes have "promoters," beginning sequences that serve as an on/off switch. In the case of Finnerty's antisense gene, the promoter is heat sensitive, meaning the gene is only activated when the fly is exposed to brief moments of heat. This control over the gene's activity allows Finnerty to determine what happens when the gene is turned on at specific times without interfering with earlier or later periods in development.

"We think from our genetic studies that it is not the lack of expression of this protein that leads to problems, but probably the misexpression," she explained.

Currently Finnerty is pursuing two other avenues. A single gene can encode more than one protein, and Finnerty has found that the MCC gene encodes at least two. She plans on injecting the DNA sequence of these two proteins into the fly and determine how this affects development. She is also trying to make a mutation that will affect MCC gene expression, uncovering genes that interact with her gene of interest.

It is this part of her research that will be the most difficult but possibly most rewarding. While studying specific genes in isolation can yield promising clues, biology doesn't occur in such a simplistic fashion-all genes interact with each other in complex ways, regulating each other. By generating and identifying mutations that affect the MCC gene, Finnerty hopes to uncover the pathway that the MCC gene travels.

"If the fly looks worse, then the mutation is an enhancer; it enhances the mutation," she said. "Or your fly could look better, which is a suppressor; the mutation has ameliorated the effects of the gene. The point is that enhancers and suppressors should be in the same pathway or in interacting pathways."

Outside the narrow confines of her own lab, Finnerty has been forced to confront the current state of cancer research and treatment. Four years ago, her husband died from cancer. She noted that many promising projects are not being funded, causing some scientists to leave research. Ostensibly, these studies are not funded because they are poorly designed or will not yield good results, but she disagrees. "The bottom line is that there's not enough money," said Finnerty, whose work is supported by the Winship Cancer Center and Exelixis Pharmaceuticals.

She feels that more money must be pumped into basic research. To Finnerty, this necessary increase in funding seems the only logical recourse as long as one in three Americans are at risk for cancer.

"Fifty percent of all people diagnosed with cancer die within five years. This is astounding. So despite all this talk about new treatments, very few of these treatments are magic bullets," Finnerty said. "As long as cancer ranks as a major cause of death, we simply aren't spending enough on research."

-Paul Thacker

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