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13 years ago
HUMANS SHARE CANCER GENE
 Melissa Kasheta a research technician at the University of Massachusetts Medical School does research on melanoma using zebrafish.
Scientists around the world and here in Worcester are studying the cells, brains, organs, circulatory and nervous systems, and yes — even the stripes — of the humble zebrafish to find cures for human cancers and other major diseases.
For example, looking at those dark stripes on the tiny zebrafish, one might be surprised that they may be a clue to finding the cause of melanoma, or skin cancer, in people. Yet melanocytes, the same cells responsible for the pigmentation of zebrafish stripes and human skin color, are also where melanoma originates.
Craig J. Ceol, professor of molecular medicine at the University of Massachusetts Medical School, and his collaborators at several institutions, studied the dark stripes of zebrafish to single out the gene responsible for promoting melanoma, in what could be a major breakthrough for developing drugs to fight skin cancers. Their research was published in the March 24 issue of Nature. Mr. Ceol and his fellow researchers labeled the new melanoma gene as SETDB1.
Mr. Ceol and scientists at Children's Hospital in Boston analyzed more than 2,100 tumors from more than 3,000 zebrafish to determine which gene triggers melanoma, rather than a benign mole or liver spot.
“We've known for some time that there are a number of genes that are responsible for the promotion and growth of melanoma,” Mr. Ceol said.
Researchers found that the SETDB1 gene in the zebrafish not only appeared earlier, but grew faster and invaded more deeply into neighboring muscle and spinal tissue. With that new information, researchers screened more than 100 human melanomas for the SETDB1 gene and found that in 70 percent of the sample tumors, the gene was present in high levels, indicating that SETDB1 may be involved in the formation of a majority of human melanomas.
Cases of melanoma, an aggressive form of skin cancer, in the U.S. have been on the rise. In 2009, 68,000 new cases were diagnosed and 8,700 people died from the disease.
“We study cancer genes,” Mr. Ceol said. “Cancer is a disease when genes go bad.”
Zebrafish have raised black stripes that contain the same cells as humans. The peppery appearances on the tops of the zebrafish are also melanocytes.
Because of the new finding, Mr. Ceol said, “There are already people working on developing drugs to treat melanoma. Instead of developing gene to drug, they're developing drugs to genes.”
Close to Mr. Ceol's lab at UMass Medical School-Lazare Research Building , approximately 3,000 zebrafish swim inside 300 freshwater tanks in the fish room. The room temperature is kept in the low 80s, and every fish tank has carefully labeled, genetically distinct lines. One female zebrafish can lay between 200 and 300 eggs a week.
Zebrafish typically lay their eggs in the morning. Scientists can begin injecting RNA and DNA with a microscopic needle within an hour that the eggs are laid. The room and tank equipment are equipped with alarms because the zebrafish are so valuable.
Mr. Ceol is only one of several scientists at UMass who have been doing medical research with zebrafish. Nathan D. Lawson, Scot A. Wolfe and Charles G. Sagerstrom are also studying them, hoping for breakthroughs in expediting cures for all sorts of human diseases. Zebrafish are popular with researchers because the fish are transparent, and have very rapid early development. Researchers can observe their brain and veins from the outside.
Mr. Lawson, an associate professor of gene function and expression, heads up a lab that studies the formation of blood vessels, arteries and veins in zebrafish.
“We study vascular development,” Mr. Lawson said. “The formation of new blood vessels is really relevant to every major disease in the U.S. In zebrafish, the embryos are transparent. We watch the tiny embryos with big specialized microscopes. The embryos develop in a dish externally, so this makes it very easy (to see through a microscope). Another major benefit is that we have a complete cardiovascular system in 36 hours with the heart beating and blood pumping around.”
Mr. Lawson said scientists essentially study normal development and then perturb the genes to create mutant cells to study.
“Then we go back and figure out what genes were affected,” Mr. Lawson explained. “We're trying to figure out how blood vessels become different.”
There are hundreds of open labs in the research building, and Mr. Lawson's labs are next to Mr. Wolfe's labs. Mr. Lawson and Mr. Wolfe have a joint grant from the National Institute of Health — as well as a pilot grant from UMass — to study proteins that target specific sequences of genes.
“Collaborations are everywhere up and down this hall,” Mr. Lawson said. Mr. Wolfe comes at researching zebrafish a bit differently from the others. His lab is working to create tools that modify gene function.
“Mutants turn out to be one of the most interesting things to study,” Mr. Wolfe said. “We're primarily generating these biochemical tools, and the goal is to take a specific gene and inactivate it.”
“Using zebrafish for (scientific) research was not something everybody accepted at first,” Mr. Sagerstrom said. He has been at UMass for 13 years, and was one of the first scientists to move into the research building 10 years ago.”
Mr. Sagerstrom's team uses zebrafish to study the nervous system.
“The question we ask is how in embryos some cells are set aside to become neurons,” Mr. Sagerstrom said. “Perhaps if we can learn how an embryo makes a neuron, maybe we can learn to make a neuron.”
There are about 1,000 such labs worldwide, including the seven labs at UMass, that are using zebrafish in scientific research.
“When I started, there were a half-dozen,” Mr. Sagerstrom said.
“What motivates me is looking at human disease; there's something different every day. What we're all trying to do is push boundaries,” Mr. Ceol said. “There's just a lot of cool stuff going on here.”
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