biomedical research in the late 19th century, playing a major role in establishing the germ theory, identifying pathogens, linking vitamin C insufficiency to scurvy, and modeling diabetes and pre-eclampsia. The guinea pig metaphor lives on but today, mice, rats, fruit flies, nematodes, and zebrafish dominate as model animals. But there are many new model animals on the research horizon, chosen because they can model human diseases in novel ways or because they have special abilities that humans lack. In this series, we will explore a few of the nontraditional animal models, and their potential in the lab.We still talk about guinea pigs as experimental subjects yet you'd have a hard time finding one in a modern research laboratory. Guinea pigs were first used in
Consider the thirteen-lined ground squirrel, Ictidomys tridecemlineatus, which hibernates for up to six months. During that time, the squirrels don't eat or drink, hardly move, and their heart rate drops to only 3-5 beats per minute so little oxygen is circulated. Yet they don't lose muscle tone or bone density, their blood doesn't clot, and their organs are back to normal within two hours of arousal in the spring. "Nature has designed solutions for all these things of biomedical interest. We just have to figure out what they are," said Jessica Otis, an ASCB member who is now a postdoc at the Carnegie Institute. She was first introduced to hibernation studies of squirrels in Hannah Carrey's lab at University of Wisconsin-Madison. "It interested me because I found the physiology of hibernation so fascinating, but it also has so many biomedical applications."
For example, the NIH Institute of Neurological Disorders and Stroke has funded research investigating ground squirrel physiology, believing that their low blood flow to the brain during hibernation can serve as a model for strokes. By learning what protects the squirrels from brain damage during long periods with low oxygen, scientists can learn about factors that could protect the brains of stroke victims. Understanding how the ground squirrel is able to hibernate can provide insights not only for patients with strokes, but also those with ischemia, transplants, heart attacks, osteoporosis, obesity, blood clotting disorders, or complications that come with prolonged bed rest.
Yet there are challenges to working in a nontraditional model, according to Otis. Though the ground squirrel genome has been sequenced, it's not well annotated. And wild ground squirrels have far greater genetic diversity than inbred lab mice, which are genetic clones. Plus squirrels only breed once a year so it's expensive to breed them in captivity.
Luckily, squirrels are officially pests and require no special permits to collect, although the researchers carefully followed the university's animal care protocols. They are also fairly easy to catch, Otis said. "We would go to golf courses and see which burrow they popped down into, then flood them out by pouring water in the burrow." She and her colleagues, wearing leather garden gloves, would grab the squirrels as they abandoned their holes. "To get a little bit of genetic similarity we would collect pregnant females in the spring so they would give birth in captivity and we could raise the pup litters," she explained.
The ground squirrel model runs on an annual summer-winter cycle. As controls, nonhibernating summer squirrels are often compared with their hibernating winter counterparts, so it can take years to collect samples. "You have to be a very good planner. There are other models of hibernation that are facultative, such as the Syrian hamster, where if you change the light cycle and their availability to food, you can induce hibernation. It's a different model because they're getting different cues for hibernation," Otis said. In her mind, the real advantage of ground squirrels is that they have evolved all these mechanisms to control physiological functions, controls that could be immensely valuable for human patients. "That's fascinating to me. Comparative physiology is amazing in that way," Otis said.
While ground squirrels may offer new behaviors and new biological mechanisms to explore, they also have one additional cardinal virture—they are not mice or Drosophila or any of today's popular and, some say, overused lab models. Critics have pointed out how much published research is based on a single lab animal, like the mouse. "The truth is that for some questions, mice give you a very nice and easy model system for understanding what's happening in humans, but mice are mice, and people are people. If we look to the mouse to model every aspect of the disease for man, and to model cures, we're just wasting our time," Clif Barry, Chief of the Tuberculosis Research Section at the National Institute of Allergy and Infectious Diseases, told a Slate reporter.
Jessica Bolker, biology professor at University of New Hampshire, believes using a range of animal models should be encouraged. In a Nature editorial, Bolker warned that "studying only a few organisms limits science to the answers that those organisms can provide... We need to broaden our range of models to include species such as Antarctic icefish, comb jellies, cichlids, dune mice and finches that are naturally endowed by evolution with features relevant to human diseases."
Squirrels have their problems, Otis acknowledges, but she is fascinated by hibernation biology and is eager to return to the subject, perhaps working with ground squirrels again after her postdoc training. Otis says that she's learned a tremendous amount from working with mice and zebrafish in her postdoc position at Carnegie but once she has her own lab, Otis would like to apply some of these new advanced techniques and technologies to the ground squirrel model.
"I think there's a lot of value to looking at nontraditional models, and as technology progresses it will be less of a challenge to work with them. I think it's an important thing to consider when you're designing experiments: Am I using the best model? Should I branch out? Is it feasible to do so?" Otis said.