Why zebrafish represent a miracle for the economics of lab-testing — and why rats are overpriced.
By Mallory Locklear
Ellen Van Rooijen, a researcher at the Zebrafish Lab, holds translucent zebrafish at Boston Children’s Hospital on April 17, 2015. (Photo: Scott Eisen/Getty Images)
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Walking into the fish room is like walking into an entirely different climate — a little microenvironment tucked away inside a large research building. It’s hot, around 80 degrees, and the air is thick. It smells exactly how you would expect a fish room to smell, but there’s something rather pleasant about the sound of water trickling into the room’s 2000 fish tanks. This particular room, part of Howard Sirotkin’s lab at Stony Brook University in New York, is home to 20,000 zebrafish — the little fish that has become a crucial research tool.
Sirotkin, an associate professor in Stony Brook’s department of Neurobiology and Behavior, studies the genetics of early development, including genetic and epigenetic factors that determine what undecided cells (like neural stem cells) will eventually become, plus how different genes contribute to behavior. Like many other scientists in his field, Sirotkin does his research with zebrafish.
“The zebrafish model was developed because it’s a vertebrate where we can do forward genetics as a means of identifying genes,” Sirotkin says, “so what that means is we can identify genes that are involved in particular biological processes by pinpointing mutations in the genes that affect those processes of interest in some way.”
The zebrafish, related to the minnow, is typically around one inch long, has an average lifespan of almost four years in captivity, and offers a number of qualities that make it an ideal model organism for research.
Maybe the biggest research advantages of zebrafish is the species’ expansive reproductive capacity.
First, they’re vertebrates, which means that “the structure of their genomes, their physiology, and their cellular make-up are more similar to mammals, including humans, than some of the invertebrate models, like fruit flies or worms, that offer similar advantages in terms of genetic approaches or tools,” Sirotkin says. Another benefit of the zebrafish model is the transparency of the embryos, which allows researchers to observe their development easily and non-invasively, as it happens — including the division and movement of cells as well as biological processes like neuronal activity.
Maybe the biggest advantages of zebrafish, though, is the species’ expansive reproductive capacity. “One of the benefits is the number of offspring they can produce,” says Cara Moravec, a postdoctoral fellow in the genetics department at the University of Wisconsin–Madison. “A single female can lay several hundred eggs per week,” according to Sirotkin.
This is actually why the fish room is so warm: Higher temperatures are better for encouraging zebrafish to lay eggs. “They’re hearty, but they can be picky when it comes to laying,” Moravec says. There’s a sign on Sirotkin’s fish room door reminding those coming in and out to close it quickly and tightly in order to maintain the temperature.
And providing the zebrafish with the perfect environment for egg-laying is important, since the rapid and prolific reproductive abilities of the fish are a valuable research tool. Take drug screening, for instance. When trying to determine what drugs might be potentially therapeutic for a particular disorder, a researcher first has to observe how administering that drug changes a specific behavior. But when thousands of drugs have to be tested, that process can become quite long. Zebrafish larvae, because they’re aquatic, breathe through their skin and can thereby ingest small molecules efficiently. Therefore, it’s relatively easy to put a drug in the water along with the zebrafish larvae and observe whatever effects it has on behavior.
Because these fish breed so quickly and in such large numbers, the whole process can happen incredibly quickly. “If you’re working with rodents, you’re essentially testing a single drug on one rodent at a time. It’s very slow and could take months,” Sirotkin says. “We can test hundreds of compounds in an afternoon. Over time, tens of thousands of compounds can be screened. So it’s really powerful, particularly as a tool for looking for potential therapeutic compounds for disorders that influence behavior.”
“It’s a transitional system in my mind,” according to Moravec. “You’ll want to eventually screen the drugs on higher mammals, but this is a great way to pinpoint potential candidates first.”
Another major benefit of studying zebrafish is the very low marginal cost: With many other research animals, housing ever-more specimens would lead to greater and greater costs. Not so with zebrafish: Adding an additional zebrafish doesn’t significantly increase the total cost of caring for them all. “Once you have a certain infrastructure, having the aquaculture set up and having the fish manually fed twice a day, there’s a very good scaling factor,” Sirotkin says. “The cost of maintaining 1,000 fish is not much less than having 20,000 fish, whereas with rodents every cage requires considerably more work and expense.”
“We can test hundreds of compounds in an afternoon. Over time, tens of thousands of compounds can be screened.”
And that expense can be prohibitive. Most universities have animal facilities that house research rodents, and these facilities are staffed by professionals who feed, clean, and care for the animals. Typically, universities charge labs by the animal or by the cage to cover the cost of housing and maintaining the animals. In some cases, zebrafish are housed in the animal facility, but in many cases, like Sirotkin’s, the research labs maintain their own fish colonies, circumventing these university costs. “It costs our lab almost 53 cents per cage per day to house mice,” says Jaime Kaminer, a postdoctoral fellow at Rutgers University. For rats, the per diem rate is 95 cents per cage. And these prices are mirrored elsewhere. At Clemson University, rat testing costs researchers 68 cents per rat per day. At the University of Minnesota, $2.02 per cage per day. At The Ohio State University, $1.47 per cage per day. At the University of Arizona, $1.62 per cage per day. At Stony Brook University, where Sirotkin’s lab is, rat housing costs 42 cents per rat per day. And at Boston University, rat housing costs 75 cents per day — whereas zebrafish only cost 18 cents.
Buying zebrafish is also way cheaper than buying rodents. A commonly used mouse breed cancostanywhere from $20.00 per animal to well over $200 depending on the sex, age, and reproductive stage — and that’s without any sort of special genetic manipulation. Similarly, a popular rat breed cancost between $14 and $120. Rodent research has created a big business: Three of the largest companies that sell rodents for research purposes are Taconic Biosciences, the Jackson Laboratory, and Charles River Laboratories, the latter a publicly traded company that, in 2015, boasted $1.36 billion in revenue.
That kind of money and those kinds of companies, though, don’t really exist in the zebrafish research world. “There are a couple of stock centers around the world that serve as repositories for mutant strains,” Sirotkin says, “and you can order wild-type or mutant transgenic lines from them. But typically, for fish labs, people more often obtain founders and just breed them themselves because it’s much more cost effective.” Often, when starting a new fish colony, researchers will simply get new zebrafish from other research labs as a professional courtesy. “The community is really supportive,” Sirotkin says. “It was founded on the principles of being good collaborators and developing lots of community resources to share.”
Further, Moravec believes that the economic benefits of zebrafish will get even better as technology advances. “The toolbox is getting better,” she says. “For example, CRISPR is definitely the cheapest and most efficient method we’ve used.” The CRISPR/Cas9 system is a relatively new way of targeting and editing specific genes. “Now you can complete the cloning process in less than a day or even in just a few hours depending on the method you use,” Moravec says.
Moravec also points out a potentially overlooked benefit of zebrafish. “Apparently, according to some studies, fish tanks relax people,” she says. “Maybe zebrafish geneticists are better off because we have a whole lot of fish tanks leading to greater relaxation at work. Also, the fish are just cute.”