I’m sure you know that most biomedical research has been conducted on mice. Well, that might have been a terrible mistake with weighty ramifications for the study of sepsis, burns, and trauma. The reason for this potential tectonic shift comes from a newly published paper in Proceedings of the National Academy of Sciences by Seok et al. (2013) that uncovered just how dissimilar the immune responses of mice are to those of man.
The abstract reads:
A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.
Gina Kolata of the New York Times writes,
The paper, published Monday in Proceedings of the National Academy of Sciences, helps explain why every one of nearly 150 drugs tested at a huge expense in patients with sepsis has failed. The drug tests all were based on studies in mice. And mice, it turns out, can have something that looks like sepsis in humans, but is very different from the condition in humans.
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, said Dr. Clifford S. Deutschman, who directs sepsis research at the University of Pennsylvania and was not part of the study.
The ramped-up immune system releases its own proteins in such overwhelming amounts that capillaries begin to leak. The leak becomes excessive, and serum seeps out of the tiny blood vessels. Blood pressure falls, and vital organs do not get enough blood. Despite efforts, doctors and nurses in an intensive-care unit or an emergency room may be unable to keep up with the leaks, stop the infection or halt the tissue damage. Vital organs eventually fail.
The new study, which took 10 years and involved 39 researchers from across the country, began by studying white blood cells from hundreds of patients with severe burns, trauma or sepsis to see what genes were being used by white blood cells when responding to these danger signals[...]
The study’s investigators tried for more than a year to publish their paper, which showed that there was no relationship between the genetic responses of mice and those of humans. They submitted it to the publications Science and Nature, hoping to reach a wide audience. It was rejected from both.
Still, Dr. Davis said, reviewers did not point out scientific errors. Instead, he said, ‘the most common response was, ‘It has to be wrong. I don’t know why it is wrong, but it has to be wrong.’
Amazing. I’ve written about the presumptuousness of scientists before, the “peer-reviewed” false significance in biomedical research that Dr. John Ioannidis believes to be more common than truly significant findings, but this might serve to humble scientists in a way not seen in ages. However, don’t expect many of them to go quietly into the night. In fact, some are griping that this Seok et al. only isolated one of many mice strains and fallaciously generalized their findings to all mice strains. It is true that the C57BL/6 (or B6) was the only strain studied, but, to be fair, it is the most common strain of lab mouse. Two years ago, a prominent lab mouse breeder estimated that somewhere between half and two-thirds of all its orders were for these “B6″ mice, even though approximately 400 strains of inbred mice exist. So, this is a big deal, if it holds up under further scrutiny.
Therefore, how much research into cancer, heart disease, and autoimmune diseases will need to be tossed out the window because of the terrific assumption that the immune systems of mice and men respond similarly? Common sense tells us that such a purported similarity sounds absurd on the face of it, but scientists know best, no matter how nonsensical their findings. Except that, prior to this latest bit of research, no systematic study had ever been conducted as to how well mice mimic man’s immune response. The fact that Nature and Science, the two most prestigious science publications, rejected this paper, not for any demonstrable lack of merit, but out of stodgy arrogance, only further proves why the general public should be leery of the self-professed excellence of “robust” findings and the sanctity of the peer-review process.
Science is an extraordinary pursuit, no doubt, but this latest bit of research further demonstrates why scientists generally need to get off their sanctimonious pedestals and admit that they assume quite a lot, hope for a good bit more, but, in fact, know very little. Moreover, the public should take every “statistically significant” peer-reviewed finding from every acclaimed scientific journal with a grain of salt instead of trumpeting it as gospel truth. And last, but not least, never trust a rat—or a mouse, for that matter.