Are animal models a good analogy for humans? A recently published study of mice suggests that there may be problems

Are animal models a good analogy for humans? A recently published study of mice suggests that there may be problems

To set standards, animal models are frequently used. Such use allows researchers to investigate disease and injury states in ways which would be considered unethical to inflict on humans. For example, to determine some threshold injury or disease state, various groups of animals may be exposed to widely varying concentrations of the particular molecule being assessed. It is assumed that because the animal commonly used is a mammal, as are we, that the biochemical and metabolic processes of the two different species have enough in common that useful data will be generated to, say, set standards of some sort (e.g., "no effects" levels, exposures that impact fertility or birth defects or cause cancer) or show the effectiveness of drugs. But, is such data valid? Recently published work on mice suggest there may be problems.

The study discussed in this blog grew out of a much larger effort to understand why nearly 150 clinical trials of drugs targeted at sepsis in humans failed. Sepsis, a potentially deadly reaction that occurs as the body tries to fight an infection, afflicts 750,000 patients a year in the United States, kills one-fourth to one-half of them, and costs the nation $17 billion a year. It is the leading cause of death in intensive-care units.

These drugs were developed using mouse models and the drugs were all intended to control excessive immune responses. Potentially deadly immune responses occur when a person's immune system overreacts to what it perceives as danger signals, including toxic molecules from bacteria, viruses, fungi, or proteins released from cells damaged by trauma or burns. Such immune system responses may also play a role in heart disease and cancer.

The new study indicates that mouse models do not accurately reflect the genetic and proteomic responses to acute inflammatory stress in humans. As noted, the research grew out of a larger project to characterize human inflammatory response to serious trauma (e.g., burns, car accidents, infection). The project was aimed at studying the multitude of genetic responses that result from these acute inflammatory stimuli in humans to ascertain the key biophysiologic response to such inflammation. As often happens in science, serendipity intervened.

When reviewers rejected one of the group's papers because it failed to show that events in humans were reproduced in mice, the researchers began to question the relevance of mouse models. So they decided to compare their data about human responses to that from corresponding murine (rodent) model systems. The researchers compared changes in the expression of thousands of genes, the time course of those changes (using software designed to normalize the different time frames in which responses occur in mice and humans), and the regulation of major signaling pathways involved.

In humans, the genetic response was highly consistent even though patients were subjected to different inflammatory stimuli and different subsequent treatments, suggesting that the drugs targeting these molecular mechanisms could work for multiple inflammatory diseases. The common patterns seen in humans were not reproduced in mouse models, and the responses among the various mouse models varied widely. The researchers also compared existing gene expression data from human patients and corresponding mouse models for several acute inflammatory diseases, including sepsis and acute respiratory distress syndrome, as well as response to injury. Again, mouse models poorly mimicked the response among humans, which were highly consistent. What was seen was that different conditions in mice - burns, trauma, sepsis - did not engender the same response. Each condition used different groups of genes. In humans, though, similar genes were used in all three conditions.

Learned commentary on the study were highly varied. Some noted that the "commonality" alleged in various mouse models of humans was set too low, that there needs to be a higher degree to which a model reproduces human disease in terms of molecular mechanisms, rather than just phenotype (the observable physical or biochemical characteristics of an organism). Critics noted that the research focused on one strain of mice, and that until data was in on other strains, it was too early to draw sweeping conclusions. Other critics noted that the paper was correct insofar as the behavior of white blood cells goes, but that it was improper to draw any sweeping conclusions about other bodily organs (e.g., lungs, liver, heart, brain).

What does this mean, then, if anything, for litigators? Now that Daubert has come to California, one has to think in terms of genes, RNA, molecular pathways etc. It is not enough to allow an expert to waive his/her hands and say X causes Y without asking --- why is that? Explain to me exactly how disease Z comes about in terms of genes being utilized or blocked, molecules conveying messages, modifications happening to normal pathways.

The study can be found at http://www.pnas.org/content/110/9/3507.