Richard White / Children's Hospital Boston
Scientists use transparent zebrafish to study internal organs and disease
progression in living organisms. Click on the image for a larger version.
Hot on the heels of see-through frogs, researchers at Children's Hospital Boston have bred see-through zebrafish that put tumors and stem cells on display as they grow. The transparent lab animals already have started to provide insights into how cancer spreads - and how it can be treated - in not-so-transparent human beings.
The fish breeding project and its application to medical research are described in Thursday's issue of the journal Cell Stem Cell as well as a news release from Children's. Zebrafish, like frogs and mice, are frequently used as experimental models for diseases and biological processes seen in humans as well.
Usually, researchers allow the animals to get a disease analogous to the human malady, then kill and dissect the animal. But when it comes to cancer progression, scientists would prefer to see how the process works in a live animal.
Scientists have used transparent zebrafish embryos for that purpose, but when the fish reach adulthood, they turn opaque. That effectively closes the shutters over a valuable window for research. "Everything after four weeks has been invisible to us," Dr. Richard White, a clinical fellow in Children's stem cell program and an instructor of medicine at the Dana-Farber Cancer Institute, explained in today's news release.
White and his colleagues in Leonard Zon's laboratory at Children's created transparent adult zebrafish by mating two existing breeds: One, known as the "roy orbison" zebrafish, has black and yellow pigment. The other, known as "nacre," lacks the black pigment but has a reflective pigment as well as yellow. Some of the offspring from the match were born without either the black or the reflective coloring - leaving only a see-through yellow. White named the new strain "casper" - presumably after the friendly cartoon ghost.
The see-through fish were first used in an experiment tracking how cancer spreads. "The process by which a tumor goes from being localized to widespread and ultimately fatal is the most vexing problem that oncologists face," White explained. "We don't know why cancer cells decide to move away from their primary site to other parts of the body."
White created a fluorescent skin tumor in the fish's abdominal cavity, then put the fish under a microscope. Within five days, the cancer cells began to spread. White could even see how individual cells metastasized. The cells seemed to home in on the fish's skin after leaving the abdominal cavity.
"This told us that when tumor cells spread to other parts in the body, they don't do it randomly," White said. "They know where to go."
The finding suggests future therapies that would somehow fool cancer cells into missing their targets, thus heading off metastasis.
White also studied how blood-forming stem cells migrated through the see-through fish. First, he irradiated the fish's bone marrow, then he transplanted fluorescent stem cells from another zebrafish. Once again, he could see how the individual cells migrated back into the bone marrow.
This method could be used to test how different drugs or gene therapies can make bone marrow transplants more effective in humans, White said.
Looking beyond cancer research, White noted that the fish's brain, heart and digestive tract are visible, which would allow for the study of genetic organ defects from early embryonic development through adulthood. That could provide insights into the progression of genetic diseases ranging from Alzheimer's to inflammatory bowel syndrome, he said.
Like see-through frogs, glowing kittens and other members of the weird-science menagerie, transparent zebrafish may at first sound like silly sorts of pets - but once you know what they're being used for, the idea isn't silly at all. See-through creatures are providing new ways to bring biological research to life - literally as well as figuratively.
"What happens in a living organism is different than what happens in a dish," White said.