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A University of Wyoming researcher has discovered what could be an important insight in reversing cancer-associated properties of cells caused by genetic mutations in humans. And he did it using worms.
David Fay, a UW professor of molecular biology, studied a strain of nematode worm (Caenorhabditis elegans, which are transparent and approximately 1 millimeter in length) that carries a gene mutation similar to one that is inactive in many human cancers. Dubbed “LIN-35,” this gene in worms is similar to the “pRb” protein gene in humans, he says.
Fay, along with his doctoral student, Stanley Polley, identified these genes by systematically inhibiting most of the genes in the worm genome. Through this process of elimination, the two discovered that defects caused by mutations in the LIN-35 genes could be reversed by inactivating a small number of other worm genes.
“If these genes were inactivated in a human with cancer, it could potentially reverse their (cancer cell) tumor potential or cancer-associated traits,” Fay says.
Fay’s discovery is published in the August issue of the Genetics Society of America (GSA) journal, GENETICS, which hit newsstands yesterday (Aug. 9). For a full text of Fay’s research, go here.
GENETICS, a peer-reviewed, peer-edited publication, is one of the world’s most cited journals in genetics and heredity. Founded in 1931, the GSA is the professional membership organization for scientific researchers, educators, bioengineers, bioinformaticians and others interested in the field of genetics.
“This research is important because it offers possible new ways to shut down the genetic machinery that contributes to cancer growth and progression,” Mark Johnston, editor-in-chief of GENETICS, says in the magazine’s press release. “The causes of cancer are complex and varied, so we must approach this disease from many angles. Using simple ‘model organisms,’ such as nematode worms to find new drug targets, is becoming an increasingly important and effective strategy.”
“I’m excited to identify a number of genes that may functionally interact with a well-known tumor suppressor gene (pRb in humans),” says Polley, from Milwaukee, Ore., a doctoral student in UW’s Molecular and Cellular Life Sciences program.
Process of elimination
The contribution of C. elegan worms to science is enormous, Fay says. He notes that three Nobel prizes -- two for medicine and one for chemistry -- in a 10-year period were given to scientists whose research centered on the use of worms.
During his research, Fay identified 17 genes in nematode worms that can suppress multiple, distinct LIN-35-synthetic phenotypes. Phenotypes refer to how an animal looks or behaves. When two or more mutations show a phenotype in a combination that they fail to show when alone, that is referred to as a synthetic phenotype, Fay says.
Fay systematically inactivated other genes in the genome of the mutant LIN-35. As the various genes were inactivated, Fay identified those genes that led to a reversal of defects caused by the loss of LIN-35. To Fay, these genes’ ability to suppress LIN-35-associated phenotypes in the worm suggested these genes may be useful targets for anti-cancer therapies in humans.
Humans possess roughly 10 trillion cells, and the human genome is encoded by more than 6 billion base pairs of DNA, Fay says. In every cell division, cells have to replicate their entire DNA.
“What are the chances something will go wrong when cells replicate their entire genome?” Fay asks. “No matter how well our cellular machinery functions, it makes mistakes. The bottom line is that acquiring mutations that can lead to cancer is sort of an unavoidable fact of life.”
An added bonus
In addition to having his paper published, Fay’s research will reach an even wider audience. With articles called “primers,” GENETICS has created a new educational resource to connect cutting-edge research with critical thinking at the undergraduate level.
The first primer article, tied to the paper written by Fay and Polley, introduces the concepts of reverse genetics. The primer article, which college genetics professors are encouraged to include in their syllabi, contains explanations of scientific concepts involved; suggestions for how to use the information to teach class lessons; and questions for classroom discussion, according to a GENETICS press release.
“I feel really pleased about that,” Fay says of his work being made available to a wider audience. “The whole point of publishing a paper is to let scientists learn. But, usually that knowledge bypasses people earlier in their (scientific) careers. I’m glad they’re using this as a teaching tool.”
Fay half-jokingly says he expects to receive emails from undergraduate students at other universities, telling him everything that’s wrong with his research.
And while he’s pleased with his breakthrough research, Fay says the world of science moves slowly and projects it may be at least 10 years before his concepts can be translated effectively and safely to humans.
“This is how science works,” he says of principles that have to be proven and numerous clinical trials that have to take place. “It’s up to people who work in more translational fields to start to make those leaps.”