In the colors of the zebrafish, hopes for human health

WSUV scientists seek secrets in genetic code




You could think of DNA as a panel with thousands of buttons that control every aspect of a human’s — or any other creature’s — biology.

Each button, or gene, does something different, and if you push more than one button at a time you get an even wider variety of results.

Those buttons control everything, like the functioning of your internal organs, the color of your hair and the pigment in your skin.

With all the variety, it’s almost impossible to understand how the system works as a whole.

That’s why scientists like Cynthia Cooper and Lauren Clancey at Washington State University Vancouver usually take a much smaller approach.

They investigate just a handful of genes at a time.

Cooper, an assistant professor of molecular genetics, and her friend and lab technician, Clancey, are investigating a set of genes that could one day help doctors control aspects of melanoma and other skin cancers and perhaps even prevent or cure them. And the two scientists are learning about how those genes work by studying a small fresh-water fish common in the Himalayan region.

“There are probably thousands of people who work on different sets of genes all over the country,” Cooper said. “I think of it as chipping away at the problem, because the problem is huge. But one day these genes might be a way we can prevent skin cancer or treat it.”

Plenty of fish in the … tub?

In part of the lab in a cloyingly warm and humid room in the WSUV Engineering and Life Sciences building, several varieties of zebrafish swim in dozens of plastic containers called spawning pens. Other scientist friends who know Cooper’s interested in the fish’s skin pigment send them to her when they find ones with interesting mutations.

Some of the lab’s zebrafish have the typical stripes, but others are translucent, spotted or completely white.

“One of the cool things about these mutations is that you can actually see them,” Clancey said. “Often when you’re studying genetics, the mutations are internal or so small that you don’t know they’re there.”

Each change in coloration marks a difference of only a gene or two, and by watching how the fish change when those genetic buttons are pushed, the scientists learn a bit more about what happens when the same buttons are pushed in humans, Cooper said.

“Genetic differences include pigment intensity. For instance, you could have a cell that ends up being dark enough but not intense enough, or a cell that’s very intense but not very dark,” Cooper said. “So we study all these mutations and find new genes. It’s a slow process, but we’re very interested in the basic science of these cells.”

The gene sequence in the fish is much smaller than the human genome, but parts of the sequence often do the same thing in many animals, including people, she added.

If the two researchers find cells that could help doctors treat skin cancer, they’ll publish a paper and let others work on a medical cure. That’s typically the process in basic science.

But basic science is still a critical component in building a treatment.

Faulty signals

In melanoma, the cell that produces pigment for skin, hair and eye color gets damaged. A false genetic trigger might tell the cell to reproduce itself endlessly or to do other things it’s not supposed to, Cooper said.

“Some things that happen when the cells become pre-cancerous –they stop receiving signals to stop them from growing, and the cells tend to migrate to places they’re not supposed to go — like to a person’s brain,” Cooper said. “They’re not supposed to move at all, but they do, and they go set up camp in other parts of the body.”

Exposure to too much sun, smoking or even eating the wrong things could all play a role in whether somebody develops skin cancer or not. Sometimes, the genes just go awry for no apparent reason, she said.

“So off the top of my head I’d say there’s probably 10 to 15 genes that are important to the development of these cells and how they work,” Cooper said. “But maintenance, the signals that these cells get, that could be a completely different set of genes.”

One thing scientists might find while studying different mutations in the fish is a botched genetic sequence that actually does something beneficial, Clancey said.

“If a mutated gene kills off melanocytes (the cells that produce skin pigment melanin), which is one thing that’s malfunctioning in skin cancer, then we could possibly use that to target and specifically kill off just one kind of cell through some sort of gene therapy,” Clancey said. “If you know how to target those (cancerous) cells to die, it would be a pretty useful tool.”

Fish teachers

The researchers don’t kill the fish when studying them.

Zebrafish are transparent until they’re two to three weeks old, when the pigment starts to take over and give the fish its coloration.

Studying eggs under a microscope is fairly simple, because eggs don’t move. But fish?

“We drug them to make them stay still,” Clancey said with a laugh.

What the two scientists are looking for are developmental changes as the fish grows, beyond just the change in the animal’s markings.

“We had one mutation that was lethal at eight days if it was able to make two copies of itself,” Cooper said. “Things like that, we need to understand more about what they might do in a larger model. You always have to think about what’s unique about that cell, what does it do with other cells to move forward.”

The research could also net results for things far beyond skin cancer. Some aspects of pigment genetics are associated with sight and hearing and could be used to help people who are losing those senses.

“I have a friend that’s losing her sight and hearing,” Clancey said. “Also grandparents, when they have a hard time hearing and seeing you, there are genes that could be associated with this that could actually help regenerate those senses.”

As a scientist, you really never know what you might find, even in something as simple as a fish, she added.

“You take the fish and go backwards and try to understand what mutated, and you take a stab in the dark,” Clancey said. “But sometimes you learn something really important.”

Sue Vorenberg: 360-735-4457;;