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The little fish Danio rerio holds secrets to understanding how vertebrates develop, how diseases like cancer work, and how we might one day learn how to regenerate human heart tissue.

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Hosted by: Michael Aranda
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Michael: When you look at a zebrafish, you probably just see a cute, tiny fish that’s smaller than your pinky finger. But this little fish is so much more than that. You’re looking at an amazing scientific tool that has led to some major discoveries. Zebrafish have been used since the 1970s to study the development of vertebrates, and more recently, they’ve been helping scientists learn more about human diseases and maybe even develop some potential treatments. So why the zebrafish?

Well, like all fish, their genomes are similar to the human genome, mainly because we share a common ancestor. They have over 26,000 protein-coding genes, and about 70% of those genes are related to similar genes in humans. Since zebrafish have been studied so much, we know that around 80% of the disease-causing genes that have been identified in humans have at least one related gene in zebrafish. By studying what these genes do in zebrafish, scientists can learn more about what they do in humans.

And there are other reasons researchers specifically study zebrafish: They’re cheap to maintain, and the females can spawn around 200 to 300 eggs in a single week, which makes for a lot of new test subjects. More importantly, zebrafish embryos and larvae are transparent and develop really quickly.

There’s even a genetically-engineered strain of zebrafish that’s transparent through its whole life. That transparency allows researchers to see exactly what’s going on inside the fish’s body, and watch biological processes — like how cancers develop. That said, zebrafish still aren’t the perfect model for human disease — for one thing, they don’t have lungs or mammary glands. Plus, a lot of their genome is made up of duplicate genes. Some of those gene copies might have mutated and developed functions that weren’t there in the ancestor’s gene — which would make them different from the human versions. Even so, zebrafish have been able to help scientists learn about a lot of different diseases -- like melanoma, the most dangerous type of skin cancer.

Cancer develops because of mutations in specific genes that affect how cells multiply and die. And the most common mutation related to the melanoma is called BRAF(V600E). Zebrafish that carry this mutation, and also lack a tumor-suppressing gene, make good models for the disease.

So researchers can study how cancer develops in fish with the BRAF mutation, and use them to test treatments. They’ve also used zebrafish to find other melanoma-causing genes. See, sometimes, the BRAF mutation just causes benign moles instead of melanoma. BRAF might start the process, but another gene has to cooperate to actually cause the melanoma. The question was how to find that gene.

The researchers used human melanoma samples to look for duplicated genes that might cause cancer along a certain section of a human chromosome. The duplicated genes they found were then inserted into the genomes of zebrafish with the BRAF mutation. And only one gene, called SETDB1, was found to accelerate melanoma formation in the zebrafish. This discovery might lead to the creation of new cancer therapies that target SETDB1.

Zebrafish research might also be able to help with stem cell transplants. And the reason for that has to do with a compound called prostaglandin E2. In a study, researchers discovered that when certain chemicals were used to enhance prostaglandin E2 synthesis, the amount of hematopoietic, or blood, stem cells in the zebrafish increased. So, extra prostaglandin E2 might be able to help treat someone who’s getting a blood stem cell transplant, like a leukemia patient or someone with a blood or immune system disorder. Which is great news!

This discovery eventually led to the creation of a drug called ProHema that’s supposed to improve the success of hematopoietic stem cell transplants using blood from umbilical cords. Between 2014 and 2015, it went through stage II clinical trials where it was tested on patients to see how well it works. And the results are pretty promising. In patients who were taking ProHema, stem cell transplants seemed to start working earlier than the control group. So, ProHema might help improve the effectiveness of these stem cell transplants, but it still needs to be tested more.

A specific trait of zebrafish might also help scientists with regenerating human tissue. If a zebrafish heart gets damaged, it can regenerate. Even if part of the heart is removed, it’ll just form a clot at the wound site, which eventually gets replaced with new cardiac muscle. But if part of a human heart gets damaged -- like from a heart attack -- the damaged area generally just turns into scar tissue, which doesn’t pump as well as healthy tissue. If you could regenerate healthy cardiac muscle instead, you could avoid that permanent damage.

It’s still being studied, it seems like the reason zebrafish can do this and we can’t is because the injury activates their cardiac muscle cells, which then regrow the tissue. As scientists learn exactly how that’s done, the idea of human tissue regeneration might get closer to becoming a reality. So the zebrafish may be tiny. But it’s helping modern medicine in a big way.

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