Trading Up in Animal Research

So, you've been working with small animals and you want to move up to larger experimental models.

By | November 7, 2005

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So, you've been working with small animals and you want to move up to larger experimental models. Perhaps you're looking to more closely emulate the human condition, or maybe you're developing a vaccine for a specific large animal species. In any case, how do you go about it? Here are 10 things you need to do.

1. PICK YOUR SPECIES

You can work with dogs, cats, cows, pigs, horses, or chimps, among others; what you choose depends largely on your needs. Cats make good models for allergy studies, cattle are useful for prion work, and monkeys are good for research into cognition and social behavior. "For human disease, I think the pig is one of the best models there is, because its physiology is so similar to that of humans," says Max F. Rothschild of Iowa State University, and National Pig Genome Coordinator at the US Department of Agriculture. "Pigs can even get diabetes."

Inbreeding has made the dog a good model system, too, says Alexander J. Travis of the James A. Baker Institute for Animal Health, Cornell University. "Certain breeds are predisposed to osteoarthritis in the hips, others to neurological defects, and yet others to specific types of cancer. If you can use those differences between breeds to identify the genes that makes one breed susceptible to a certain disease, that's a tremendous tool," he explains.

Sometimes, a certain species will simply be more appropriate for your study. Gary Anderson of the Department of Animal Science at the University of California, Davis, chose the sheep and goat for his experiments on interspecies pregnancy, because the two species are closely related and have similar gestation periods and placental types.

2. CONTACT YOUR IACUC

US federal law requires that your university's Institutional Animal Care and Use Committee (IACUC) oversee and evaluate all aspects of animal care and use. The review process can take from a few weeks to four months; during that time the committee will ask you to describe your experiment in detail.

"You'll be asked what questions you are trying to address and to demonstrate that those questions haven't been answered before," says Michele Bailey, of the Cornell Center for Animal Resources and Education at Cornell University. "You'll have to explain: why you are using that species and not other alternatives such as cell cultures; where you are getting the animals from; how many you are getting; and what kind of facilities you'll be using," she adds.

Applications to funding agencies generally require IACUC approval (or at least a note indicating that your proposal is under review). "Investigators are given guidance about how to fill in the forms, sometimes on the form itself, typically in a training session," says Joy Mench of the Department of Animal Science at UC, Davis.

3. CRUNCH THE NUMBERS

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One thing your IACUC will consider is your sample size. "You don't want people using more animals than they have to, but you also don't want people using inappropriately low numbers so that the data is worthless and the experiment has to be repeated anyway," says Bailey.

P. Dwight Tapp of UC, Irvine, used at least 46 beagles in his study of brain aging; [J Neurosci, 24:8205–13, 2004] El Terasawa of the Wisconsin Regional Primate Research Center in Madison used 10 animals to study hormone release in rhesus monkeys [J Neurosci, 16:2563–73, 1996]; And Mehdi Tafti of Stanford University used 33 Dobermans to study MHC expression in narcoleptic animals. [J Neurosci, 15:4588–95, 1996]

Consider carefully whether you can afford to buy, maintain, and study enough animals to make the experiment worthwhile. "It is expensive to work with large samples and that has a direct impact on the statistical strength of your results," says Ina Dobrinski of the New Bolton Center at the University of Pennsylvania.

4. PREPARE TO SPEND SOME MONEY

You might pay under $20 per Balb/c mouse, but a cat will cost you between $500 and $800. And an animal that has been raised under specific conditions will cost more than a conventional animal. So, you can expect to pay around $600 for a beagle, but nearly $1,300 if the animal is "antibody profile defined." Tapp could thus have spent $60,000 on the animals alone in his MRI study. Terasawa might have topped that if his monkeys were classified "specific pathogen free"; at $7,000 each, his study would have cost $70,000 in animal charges.

Care is also pricey, says Anderson. "You could easily pay $8 to $10 a day to feed one cow. If the animal gets sick, you need to pay for veterinary care, medication, husbandry. Experiments with large animals cost more, in bold face and capital letters." (For a list of animal suppliers, check http://guide.labanimal.com/guide/product2.jsp?a=1.)

5. EXPECT SOME DOWN TIME

If you want to set up a transgenic line of goats, sheep, or cattle, for example, be prepared to wait. "In cattle, it takes nine months, the gestation period, to even determine whether or not you have a transgenic founder, and at least two years, the generation interval, to start to isolate the transgenic line. You could complete that experiment in mice in a fraction of a year," says Anderson. In some cases, you won't know for the next five years whether or not you have an interesting result. So, don't assign any postdocs to the project, because they might not finish in time.

6. CHECK YOUR SPACE

A Paucity of Tools

When you work with large animal models, your menu of genetic tools and reagents is much more limited than if you were working with smaller, more widely used species.

"You just need to look at a catalog for antibodies to realize that most are directed against mice or human proteins, but rarely against pigs, dogs, or other large-species proteins," says Ina Dobrinski of the University of Pennsylvania's New Bolton Center. "Growth factors to be used in cell culture are also in short supply. Mice and humans are the only species available, and they don't always work the same in other species."

Some proteins are sufficiently well conserved that the mouse antibody will work for the cow, sheep, or other species. Often, though, that won't be the case, and you'll end up having to make a new reagent.

At least from the genomics standpoint, however, things are starting to change. Sequence is largely limited, but different genome projects (the pig, for instance) are making rapid advances. Nevertheless, for many species, if you want to find a gene or design a primer, you'll have to rely on orthologous information from mice, humans, or another species.

Larger animals need more room. Mice (up to 25 g), for instance, need just 12 square inches of floor space per animal. But dogs (up to 30 kg) require 12 square feet, and cows (up to 500 kg), 96 square feet. Cage height is also a concern: certain animals, chimps for instance, must be allowed to swing freely from the top of their enclosures.

Animals also need environmental enrichment, including more complex and varied toys and social contact with other animals. "We want the animals to be behaviorally or psychologically healthy, so they can express their normal behaviors," says Bailey.

Technology becomes more sophisticated as well. "If you are performing surgery in a monkey, for example, you need a dedicated surgery suite with a certain configuration. Larger animals require a different set of facilities and technologies than rodents," explains Mench.

7. BEEF UP THE STAFF

Experiments in large animals usually require more and better-trained personnel. One person cannot handle a pig, and to operate on a large animal, you'll need an entire crew. When Anderson does embryonic transfers on goats, he has a staff of four on hand: two surgeons, an anesthesiologist/assistant, and a nurse. "By contrast, one person can accomplish all the above using mice and do so in a much shorter period," he says.

8. CONSIDER OUTSOURCING

Many universities have an animal service on campus, with staff and veterinarians who take care of the animals and can perform the procedures. A university with no facilities might decide to build new ones, but they are not likely to build brand new farms because of the expenses, says Rothschild. So, if you are moving to larger animals, you might want to collaborate with labs that already have facilities, such as those in agricultural universities, which tend to have the best facilities. "Surgery in large animals requires sophisticated skills; that's why some labs do collaborations with veterinarians," says Anderson. "In general, it is not worth learning a new procedure. It's easier to bring somebody in."

9. THINK BEYOND THE EXPERIMENT

The destiny of animals after the experiment will depend on what they have been used for, their health condition, and the institution's rules. All transgenic animals should be humanely euthanized. Other animals may also be euthanized as part of the research, to examine tissue, or conduct further studies. Healthy animals can be given up for adoption, while agricultural animals used for nutrition studies or for teaching demonstrations can be put to pasture.

10. CHECK THE REGS

Regulations in the United States are similar for all animals used in research, small and large, says Bailey. "Any institution doing research, or testing, or teaching with animals has to be registered with the USDA, which enforces the Animal Welfare Act, which covers a limited number of species." Adds Mench: "USDA inspects facilities at least once a year and can fine you if something is wrong."

Those who receive federal funding are also subject to the Health Research Extension Act, under the Public Health Service. "To be in compliance, you have to follow their Guide for the Care and Use of Laboratory Animals http://www.nap.edu/readingroom/books/labrats, which strives for the optimum, rather than legislating the minimum," Bailey says. Cornell's animal facility is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC), Bailey adds. "They look at every animal, in every facility, regardless of what the animals are used for. As long as you are accredited by AAALAC, there are no differences in the standards for rodents or for the larger animals."

In the United Kingdom, one set of standards covers all research animal use. "Although there are no animal-care committees in the UK, the legislation is similar, as it is in other EU member countries," says Bailey. "AAALAC is an international program, so they also do inspections in Europe as well." The UK Home Office oversees all vertebrate and invertebrate animals. "The Home Office is like our USDA, but their system is more encompassing," says Mench.

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