An article published in the New York Times on February 11 questioned the efficacy of using mice to model human diseases that involve the immune system. The article reports findings of a research paper by Seok et al. published in Proceedings of the National Academy of Sciences on February 10. The researchers assert that years and billions of dollars were wasted studying mice.
So should we scrap mice as a model system for human disease, or is there more to the story?
The original paper compared the genetic responses of humans and mice following an injury, such as a burn. Biomedical researchers assume that if mice and humans have a similar genetic response to an injury, then treatments that are effective on mice should also be effective on humans. Seok et al. found that mice had a much different genetic response than humans following an injury, and concluded that mouse models are poor representatives of the human inflammatory response, and thus the reason many therapies fail to translate from mice to humans.
The study results are interesting and ask for further analysis and investigation. But experienced mouse geneticists point to one problem with the study, and perhaps the reason it was rejected from prestigious journals such as Nature and Science, is that it only examined one strain of mice, C57BL/6 (B6).
There are hundreds of strains of laboratory mice, each with different genetic compositions and disease susceptibilities. Each strain of mice is comparable to a single human in a population. Just as no one human is representative of an entire population of humans, no one strain of mouse is representative of all mice or much less, humans. When constructing a mouse study, ideally researchers should use several strains of mice to better model a human patient population.
To clarify, consider this example. Acetaminophen, the active ingredient in Tylenol, has variable toxicity in humans likely based on their genetic background. Some people can ingest elevated amounts of acetaminophen and experience no side effects, while other people can ingest a small amount of acetaminophen and suffer liver damage.
Response to acetaminophen has been tested in a number of mouse strains. Some strains, such as CAST, are nearly immune to liver damage from acetaminophen. Other strains, such as CBA, suffer toxic effects from the drug even at low doses. Most strains fall somewhere in between. If a researcher only used the CAST strain to analyze acetaminophen toxicity, he would conclude that acetaminophen is completely safe. If he only used CBA, he would conclude that acetaminophen is completely unsafe.
Seok et al. only tested one strain of mice yet concluded that all mice are poor models of human inflammation. If more strains had been analyzed, there might well be variation in inflammatory response, as seen with acetaminophen response.
To better model human populations using mice, an international collaboration of geneticists produced a reference panel of mice called the “Collaborative Cross.” The Collaborative Cross mixes the genetics of eight founder strains to yield over 300 new mouse strains, collectively capturing nearly 90% of known genetic variation in laboratory mice. The Collaborative Cross recapitulates the genetic diversity seen in human populations.
Researchers studying the inflammatory response to injury could use the Collaborative Cross to identify strains of mice that closely model human inflammatory response. Thus, while the B6 mouse strain appears to be a poor model for studying inflammatory response to injury, the genetic diversity present in the Collaborative Cross promises much better mouse models.
The findings of Seok et al. are solely applicable to the B6 strain of mice in the three models of inflammation they tested. They unduly generalize these findings to mouse models of inflammation in general.
Mouse models are an indispensable tool in biomedical science. We owe a great deal of our understanding of health, disease, behavior and general biology to mouse models. It’s unfortunate that the New York Times chose to publish a story on what appears to be seriously flawed conclusions based upon the available data.
Instead of “Mice Fall Short as Test Subjects for Humans’ Deadly Ills,” a more appropriate title for the New York Times article would have been “The B6 Mouse Strain Poorly Reflects Human Inflammatory Response.”