Transparent Fish Give Cancer Research a Boost, Scientists Say

Tag : reflective pigment

This spring, White and his colleagues announced that they had breda new, see-through, zebrafish. The animals' transparent skin givesscientists a clear view of developmental processes, such as tumorgrowth, in real time -- making it a valuable tool for White andother researchers.
Zebrafish, which have been used to model human disease since the1930s, are excellent research subjects: They're small and hardy,able to withstand even dirty rivers polluted with human andindustrial waste, and they breed in great numbers.
Also, fish embryos develop outside the body, which makes them idealfor studying early development. And zebrafish stay naturallytransparent for the first few weeks of life, a quality that hasproved to be critical for studying changes occurring inside a livebody.
After the first weeks of life, though, the skin of the fish startsto darken, eventually becoming opaque. White, who was tracking thegrowth of melanoma, or skin cancer, inside of the fish, wasfrustrated that the window of time for observation was shuttered sosoon.
"I thought, if I could visualize what's going on inside the animal,I could identify the changes occurring when a tumor gets started,"White recalled. "By the time one of my patients presents withcancer, the tumor is already a billion cells. Could we identify theearliest stage? Could we create a fish that's transparent?"
It turned out that he could. Zebrafish skin contains three possibletypes of pigments--reflective, black, and yellow. White mated amale from black-spotted breed with no reflective pigment, called"roy orbison," with a female from a breed called "nacre" -- theFrench word for pearl -- that had no black pigment. The offspring,with only yellow pigment in its skin, looked clear.
It took about a year of cross-breeding to develop the Casper fish.But one day, the researchers saw it swimming around in its tank,about six weeks old and still see-through.
The news and excitement spread quickly through the lab, and thenbegan making its way through the zebrafish research community.
"We were completely in awe that it worked quite as easily as itdid," said Anna Sessa, a lab technician and co-author of thezebrafish study, published in the journal Cell Stem Cell inFebruary.
"It's as clear as day," Sessa said. "You can see the heart, aorta,spine, gills. And under a microscope you can see just abouteverything."
The Casper model has been awash in attention since the Februarypaper was published. Now, other scientists are increasingly usingthe Casper fish to research a range of subjects such as bloodvessels, brain tissue and intestinal development.
Since February, White has already had about 50 requests fromscientists, many of them abroad, who want to use the Casper embryoso they can grow their own fish for research.
Nathan Lawson, associate professor of the Program of Gene Functionand Expression at the University of Massachusetts Medical School,is one of those scientists. He's growing Casper fish to studyangiogenesis, the growth of blood vessels. The new Casper line hasallowed him to expand his research from embryos to adult animals.
"We need to start to transition to adult disease models in thefish," Lawson said. "The Casper fish is one important tool thatwill allow us to get there."
White now uses the fish to better understand the process by which atumor evolves from a small clump of cells incurable cancer.
He takes a tumor from one fish, minces it up into isolated cells,and then treats it with chemicals, before implanting the cells intothe flank of a Casper fish. Sometimes, he'll also transplant thetumor and then treat the whole fish with chemicals. The goal is tofind a chemical combination that slows or halts tumor development.
Every few day, he gives the fish an anesthetic that makes itsleepy, and puts it under the microscope to observe the tumor.
"A lot of these chemicals tell us about the biology of how tumorsform," he said. "If a chemical interferes with a pathway, it tellsus about melanoma."
He is also studying metastasis, the spread of cancer to other areasof the body.
"The question I'm trying to get at is how cancer can go from a tinylittle ball of cells to becoming a widespread tumor that we can'tcure," White said. "I'm trying to figure out, how can we block thatfrom happening?"
He suspects that one way to block metastasis is to target what hecalls the "seed cells" of a tumor, cells that some researchersbelieve continually re-grow regardless of chemotherapy and othertreatment. Melanoma cells, his research also shows, undergo a sortof "homing" process. Even when the cells are implanted in the bellyarea of the fish, they tend to travel back toward the skin,suggesting that tumors don't spread randomly.
"Why do tumor cells seem to be comfortable growing in certainplaces," he said. "This tells you there has to be a complicatedinteraction between tumors and the rest of the body."
Scientists know little about this homing process of tumormetastasis. It's like a black box in the research, White said.
"Casper gives me a great opportunity to study that," he added."Where do cells go? Where do they naturally go? And can I come upwith strategies to stop that from happening?"

---- By Jenny Marder, NewsHour with Jim Lehrer