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Photo courtesy of Loyola University Chicago

This days-old fish embryo comes from the lab of Eric Schroeter, a biologist who is researching eye development in embryos. The yellow flourescent protein (center) helps scientists track gene activation critical to development. 


Fluorescent zebrafish shed light on human birth defects

by Kristen Minogue
Feb 05, 2009


ZEBRAFISH2

Photo courtesty of Loyola University Chicago

Schroeter likes to show this photo, called "red fish, blue fish," to his students.  With new advances, proteins associated with different colors are used to track different genes in the same embryo.

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Kristen Minogue/MEDILL

Zebrafish are ideal for developmental biologists to use in study, according to biologist Bryan Pickett. Just two and a half months after fertilization, the fish are ready to start reproducing and scientists can follow change through another generation.

Bryan Pickett wants to understand what makes a human brain form and why development can go so wrong when a pregnant mom drinks alcohol.

So he did what scores of other developmental biologists across the country are doing: he created his own glow-in-the-dark zebrafish.

Zebrafish don't ordinarily glow. But the genetically modified fluorescent fish are helping Pickett track development at its earliest stages, when animals are just beginning to form crucial body parts such as the brain, heart and spinal cord.

“All of development is like a giant game of telephone,” said Pickett, an associate professor of biology at Loyola University Chicago.

The key players Pickett studies are retinoic acid, a substance that tells genes when and where to start making body parts, and RaldH2, a protein that helps create retinoic acid.

Normally the game works like this: RaldH2 makes retinoic acid, retinoic acid communicates to a group of genes called the Hox genes and the Hox genes tell the early, undifferentiated embryo cells what body parts they’re supposed to become.

Alcohol disrupts the game.

According to Pickett, when ethanol enters the bloodstream, it sucks up some of the proteins responsible for making retinoic acid. When the retinoic acid level drops enough, the wrong genes are activated, resulting in drastically misshapen or dead embryos, a situation Pickett describes as “a bad game of telephone.”

Because all this can occur before a woman misses her first period, a woman who drinks alcohol could deform her embryo before she even knows she’s pregnant.

The U.S. Surgeon General has stated that five or more drinks at a time, or seven or more drinks per week, can cause growth and learning problems, but no amount of alcohol is considered safe during pregnancy.

Pickett is using a fluorescent greenish-yellow protein to track whenever RaldH2 is activated in the zebrafish.

“We think that by understanding how this system works in fish embryos, we may gain some insight eventually into how the system goes wrong in human embryos,” Pickett said.

Yellow was one of the first colors developed for tracking, but the technology has expanded to encompass a whole spectrum now.

“We have a rainbow,” said Eric Schroeter, Pickett’s colleague who helped him bring zebrafish to Loyola. “They’ve got so many different color names they now use fruit flavors.” The different colors can be used to track different proteins and development processes.

Creating genetically modified "transgenic" animals has become common practice for biologists, especially the ones who study development and disease.

“Almost anything you want to study, if you can isolate a gene for it, you can make a transgenic animal for it,” said Lynn Doglio, who works at the Transgenic and Targeted Mutagenesis Lab at Northwestern University, which makes genetically modified mice for nearby research labs.

But the popularity of zebrafish is expanding. More than 250 laboratories in the U.S. use zebrafish, according to Michael Tsang, who studies fluorescent fish at the University of Pittsburgh. And the number is growing exponentially.

Their low cost, transparent embryos and their fast growth make zebrafish appealing to researchers.

“These guys complete nine months of our embryonic development in less than a week,” Pickett said.

However, researchers are still struggling to make the process more efficient. Doglio said of all the mouse embryos injected with DNA, a scant 1 to 3 percent may actually develop into full-grown mice and inherit the injected DNA.

“You start out with a lot and you end up with a few,” Doglio said.

Pickett said the success rate for zebrafish is even lower: a mere one-half of 1 percent. But recent advances are starting to pull the figures to 20 or even 40 percent, according to Tsang.

The National Institute of Health has guidelines for lab animals, including a requirement that universities using any species in research appoint an Institutional Animal Care and Use Committee to oversee treatment.

When it comes to following guidelines, Pickett said his lab has always erred on the side of caution. And like most scientists, he said he believes the research has great potential, at least as far as studying human development is concerned.

“We’re just never going to get compelling insight into these systems without using transgenic animals,” he said.