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How zebrafish became the hottest animal in science

Proud member of the zebrafish community
Proud member of the zebrafish community
Novartis AG via Flickr

Most people think of zebrafish as little more than a cheap household pet. The fish are small — about an inch or two long — and easy to care for. Nothing special, it seems.

But inside laboratory aquariums, zebrafish are quickly gaining a reputation as utterly crucial for medical and genetic research.

Over the last few decades, the use of zebrafish in biomedical research has skyrocketed. Zebrafish breed quickly, scientists can manipulate their genes easily, and the fish actually share a surprising number of similarities with humans.

That explains why more and more major biology papers are being published using zebrafish as their organism of choice — not the lab rat, the lab mouse, or the fruit fly.

Zebrafish papers

Results for "zebrafish" or its species name "Danio rerio" in the title or abstract of medical and scientific papers contained within the PubMed database

Researchers have been able to watch zebrafish think, by making individual brain cells turn fluorescent when they're active. They've also used zebrafish to investigate the causes of rare diseases and to find potential new drugs. And that's just some of the many things they've been doing with this handy fish.

So why are zebrafish becoming so crucial for medical and genetics research? And what have we actually learned from them? Here's an overview:

Scientists can learn a lot about human diseases from zebrafish

Even though zebrafish live their lives in water and are only an inch or two long, they're not all that dissimilar from people, all things considered. Zebrafish have all the major organs that humans do — with the exception of lungs and some different reproductive parts. What's more, about 70 percent of zebrafish genes can also be found in humans.

As a result, researchers can study zebrafish to better understand how things like metabolism, birth defects, and even cancer work — and the results are often applicable to humans. So, for instance, it's relatively quick and easy to test certain drugs on zebrafish. If those experiments yield promising results, the scientists can then do more targeted experiments with rodents. And then maybe, finally, with people.

Granted, zebrafish can't help us understand everything about humans, since there are some obvious differences — the fish lack lungs, for one.

But zebrafish are more closely related to us than fruit flies, another mainstay of genetics research.

And, depending what you're studying, sometimes a zebrafish is more closely related to humans than lab rats are. "Evolution is not exactly a ladder. It’s more like a tree," says Benjamin Feldman, a biologist and the director of the zebrafish core facility at the NIH's National Institute of Child Health and Human Development. "In some cases the fish — their lineage is more in common with humans with respect to that particular gene or that particular process."

Zebrafish are ideal for studying genetic diseases

Zebrafish gif

(Video from Jeremy Swan. GIF by Joss Fong/Vox)

Scientists have mapped the human genome, but we still don't know what many of those genes do. One way to find out, however, is to study similar genes in zebrafish.

Because zebrafish are so inexpensive, small, and breed so quickly, it's easy for scientists to explore how their genes work. Researchers can randomly mutate a zebrafish's genes and then see if those mutations lead to, say, particular health problems, such as heart defects. That, in turn, gives us a better sense of how those genes work in people.

"It is possible to do this [type of genetic research] with mice, as well, but it's very expensive," says Feldman. "Only well-funded laboratories can do that, whereas people have been able to do it quite widely for zebrafish."

Over the past five years, the cost of modifying a single gene in a zebrafish has dropped from $10,000 down to about $100.

This is particularly useful for studying rare genetic diseases. One team at Duke University and Baylor College of Medicine has been sequencing the DNA of dozens of (human) babies with rare and mysterious illnesses and looking at their mutations. They then replicate those mutations — one at a time — in various zebrafish to find out which might be causing the diseases. And finding that out is hopefully the first step to someday finding a treatment or cure.

Zebrafish are very handy for testing drugs

If you drop drugs into a zebrafish's water, it can absorb it through its skin. This trait allows scientists to quickly screen a wide variety of treatments that might eventually work on people.

For example, as Virginia Hughes describes in Popular Science, Leonard Zon's lab at Harvard Medical School used zebrafish to test out 2,500 molecules that might potentially boost blood-cell counts. This took just four months — a speed that would be unthinkable if they had used lab rodents instead. One of those molecules proved promising, was subsequently tested in mice, and has now made it into clinical trials, where it may be able to help patients with leukemia.

Transparent zebrafish let us explore how internal organs work

Casper transparent zebrafish

The Casper variety of zebrafish has transparent skin as an adult. (White, RM et al. Cell Stem Cell. Volume 2, Issue 2, p. 183–189, February 7, 2008)

Researchers who study the development of embryos have long valued zebrafish — and for good reason. Zebrafish embryos are transparent, so scientists can easily watch them develop under a microscope.

But it's also possible to make adult zebrafish transparent. A team of researchers in Boston has engineered a type of zebrafish with see-through skin. This allows scientists to get a good look at its internal organs without having to do surgery or kill it. (They call it Casper.)

These transparent qualities have been exceptionally useful. For example, scientists have been able to watch zebrafish think and see how their brains work. By genetically modifying fish so that their brain cells light up when they fire, researchers have been able to track brain activity with unprecedented resolution and breadth: they can see single cells across the entire brain. (For these types of studies, they've been using zebrafish larvae, which are naturally transparent.)

How scientists make a never-ending supply of zebrafish

Zebrafish at the NIH

Racks of zebrafish tanks at the NIH. (Susannah Locke/Vox)

Zebrafish are freshwater fish originally from the Ganges River Valley, and they're not very picky. They're good at staying alive, and they're good at spawning hundreds of eggs at a time.

"They’re very hardy. They’re very forgiving," says Joseph Schech, a laboratory veterinarian in charge of roughly 200,000 zebrafish (and several other species) at the National Institutes of Health. "They are very adaptable in the wild. They live in clear mountain streams. They live in muddy rice paddies. They can do a wide range of temperature if they have time to adapt to it."

He's in charge of keeping the creatures healthy in a NIH zebrafish facility that's currently used by some 21 different laboratories. It's one of the largest zebrafish facilities in the world — a single 78–80°F room that holds about 10,000 small tanks with a total of roughly 200,000 fish. The zebrafish eat a diet of brine shrimp grown in a nearby room and can be trained to spawn on cue.

Scientists can even make designer zebrafish

GloFish zebrafish

Electric green danios, the fluorescent green zebrafish. (GloFish)

One of the more fun things to come out of zebrafish research are fluorescent varieties that can be bought in pet stores. Researchers have long been able to genetically modify fish to make fluorescent proteins for locating certain molecules in their bodies.

Now, this technology has leapt from the research arena into the pet trade. The GloFish zebrafish are available in five different colors. (However, according to GloFish's website, if you live in California, Canada, Europe, or Australia, current regulations have made it too cumbersome for the company to sell the fish to you.)

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