Rodents are the standard laboratory model system for testing the safety of treatments, chemicals and other medically important protocols and devices. Rodents share an immune system that is very similar to the primate immune system, and also share many other biological features with primates. However, all the drugs we ingest usually make a stop at the liver where they are chemically modified, and this modification step differs from rodents to humans. Some drugs are processed in very similar manners in rats, mice and humans, but many other drugs are processed quite differently. In such cases, rodents make poor model systems for how those drugs might affect human patients.
Another case where rodent models are less than exemplary is cancer studies. Experiments on rodents and rodent-derived cell lines have provided vital insights into the genetics, cell biology and molecular biology of cancer, carcinogens, or compounds that cause cancer in living organisms, have very different effects in rodents and humans. For example, some components in coffee appear to be carcinogenic in rodents, but in humans moderate coffee consumption may reduce the risk of cancer.
Another field of research trends to show very different results in humans and rodents and that field is stem cell research. Induced pluripotent stem cells (iPSCs), which are embryonic-like stem cells made from adult cells though genetic engineering techniques, very effectively cause tumors in rodents. However, in 2010, University of Georgia scientists Steve Stice and Franklin West introduced 13 pigs that might show the way toward new regenerative therapies. These pigs have been the subjects of some experiments with iPSCs and the astounding result is that adult-cell-sourced stem cells (iPSCs) don’t form tumors in these pigs.
West, an animal science researcher and assistant professor in the UGA College of Agricultural and Environmental Sciences said: “Pluripotent stem cells have significant potential for stem cell therapies . . . However, tests in mice often resulted in tumor formation that frequently led to death.” Such robust tumor formation raised concerns about the safety of iPSCs and any cells derived from iPSCs. However, to date, the vast majority of these safety tests have been done in rodent models. Given the rodents can show different results in carcinogenesis tests (a test that determines the tendency of a chemical to cause cancer) relative to humans, West and Stice wondered if these differences as translated into tumor tests with iPSCs.
To address this concern, West and Stice, and their research colleagues examined tumor formation in pigs that were actually made from iPSCs. The results were striking. According to West, “Brain, skin, liver, pancreas, stomach, intestine, lung, heart, kidney, muscle, spleen and gonad tissues from all 11 pigs tested showed no evidence of tumors.” The absence of tumor formation in these pigs suggests that iPSCs can safely incorporate into tissues without causing the formation of tumor.
The potential of such animals as model systems for medical purposes is not lost on these scientists. Steve Stice, a Georgia Research Alliance Eminent Scholar in the College of Agricultural and Environmental Sciences, said: “Being able to safely use iPSCs without the potential of causing tumors is essential for this promising stem cell therapy to become a viable treatment option . . . We now have graduate students working on making neural cells from the human and pig stem cells to help further the studies. The human stem cells were effective in a rodent model for stroke, but rodent studies are not rigorous enough to start human clinical trials.”
There are over 700 drug treatments that have gone to human clinical trials for stroke alone based on safety tests that were done on rodents. However once these drugs were brought to clinical trials, they failed all safety tests. These pigs, however, are much more similar to humans when it comes to drug processing and tolerance. Such animals are much better model systems to study strokes than rodents.
West is leading a cooperative project between the UGA Regenerative Bioscience Center and stroke researchers at Georgia Health Sciences University. “This project will improve the speed and efficiency of treatment development for stroke and many other conditions and potentially reduce the number of nonhuman primates used in research,” he said. In addition to this collaboration, Stice and West have now bred the pigs produced from iPSCs and have demonstrated that the stem cells did form germ cells (eggs and sperm), and their genes were passed to their offspring. These data opens the door for better animal-sourced tissue for human regenerative medicine such as islet cells that produce insulin for diabetic patients.
Using iPSC technology, the UGA Regenerative Bioscience Center is working with researchers at Emory University to make pigs whose cells from the pancreas demonstrate decreased rejection in human treatments. Stice noted, “The next step would be to put these pig insulin-producing cells into other animals, potentially dogs or cats suffering from diabetes—to see if it will produce insulin for them without being rejected . . . So, it’s moving forward. Never as fast as we like, but it’s moving.”