A recent toast to James Watson highlights a tolerance for bigotry many want excised from the scientific community.
A study suggests that some mouse models do not accurately mimic human molecular mechanisms of inflammatory response, but other mouse strains may fare better.
February 11, 2013|
WIKIMEDIA, RAMABiomedical scientists have long relied on experimentation in mice to explore human disease and evaluate drug candidates. But mouse models do not accurately reflect the genetic and proteomic responses to acute inflammatory stress in humans, according to a new study. The findings, published today (February 11) in Proceedings of the National Academy of Sciences, detail the oft-suspected limits of murine models for studying inflammatory response, and emphasize the need for research on human physiology.
“We’re not saying don’t use animal models, but we need to recognize that simple model systems do not reproduce complex human disease,” said Ronald Tompkins, a professor of surgery at Harvard Medical School and co-author of the study.
But Peter Ward, a professor of pathology at the University of Michigan Medical School who was not involved in the research, said the study doesn’t render mouse models irrelevant. “The fact that mice responses do not mimic the rather uniform responses in humans may be due to the fact that mice, but not humans, are inbred,” said Ward in an email to The Scientist. The inflammatory responses of mice are highly dependent on genetic background, so “until other mouse strains are studied, the authors need to be cautious in their interpretations that use of mice is irrelevant to human responses.”
The research grew out of a larger project to characterize human inflammatory response to serious trauma, such as burns, car accidents, and infection. The idea was to systematically study the storm of genetic responses resulting from these acute inflammatory stimuli in humans to discern the key regulatory elements that govern people’s response to systemic inflammation.
When reviewers rejected one of the team’s papers because it failed to show that events in humans were reproduced in mice, the team began to question the relevance of mouse models. So they decided to compare their data about human responses to that from corresponding murine 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 signalling 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. But those patterns were not reproduced in mouse models, and the responses among the models varied widely.
“Some of the same pathways may be affected but what’s important are the gene responses, and they are incredibly different,” said Ronald Davis, a professor of biochemistry and genetics at Stanford School of Medicine and a co-author of the study. “That’s significant because we’re using mice as a model system, often to develop drugs, and drugs are going to target gene products.”
The researchers also compared existing gene expression data from 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.
Some scientists have questioned how well mouse models reflect the complex physiology of human inflammatory disease. But this is the first time the underlying genomic differences have been laid bare so systematically, said Tompkins. “There is a tacit understanding that model systems reproduce human disease, but the bar is way too low. There needs to be a higher degree to which a model reproduces human disease in terms of molecular mechanisms, rather than just phenotype.”
Leonard Shultz, a professor at the Jackson Laboratory who develops humanized mouse models, in which human cells and tissues are engrafted on immunodeficient mice, and was not involved in the study, said the results are “very interesting.” But he echoed the caveat pointed out by Ward: there are no data on whether or not other mouse strains would more closely resemble human responses, Shultz said in an email.
“There are indeed multiple differences between the human and mouse immune systems and responses to inflammatory stimuli,” Schultz added. “However, the mouse strain used in the study (C57BL/6) is representative of a single individual and doesn't cover the diversity in the mouse population.”
J. Seok et al., “Genomic responses in mouse models poorly mimic human inflammatory diseases,” Proceedings of the National Academy of Sciences, doi/10.1073/pnas.1222878110, 2013.
February 12, 2013
If inbred mice are exhibiting a different gene response profiles than seen in humans, the authors' contentions would be strengthened by demonstrating that OUTBRED mice also show distinct differences.
February 12, 2013
Re: "There needs to be a higher degree to which a model reproduces human disease in terms of molecular mechanisms, rather than just phenotype.”
First, I will reiterate: The molecular mechanisms of adaptive evolution and disease are the same despite phenotype. They are nutrient-dependent and pheromone-controlled in species from microbes to man. This is best exemplified in the honeybee model organism -- an animal model readily extended to mammals. For example, the immune system and olfactory system of invertebrates (e.g., the honeybee) and mammals distinguish genetically predisposed self from non-self differences. The differences enable natural selection for the most beneficial non-self nutrients and social selection that precedes sexual selection for genetic diversity.
In stark contrast to these biological facts (above), there is a theory that mutations somehow cause evolution. That theory places the epigenetic effects of nutrient stress and social stress on the microRNA / messenger RNA balance and alternative splicings outside the context of what is now known about the molecular mechanisms involved in health and disease accross an evolutionary continuum.
It is long past time that students are taught the biological facts about animal models and adaptive evolution. The tweaking of immense gene networks in superorganisms -- like the honeybee -- that solve problems through the exchange and the selective cancellation and modification of signals is caused by the epigenetic effects of nutrients and pheromones on genetically predisposed ecological, social, neurogenic, and socio-cognitive niche construction that link gene expression to behavior and back.
Clearly, an environmental drive evolved from nutrient uptake in unicellular organisms like yeasts to nutrient intake and socialization in insects via the same molecular mechanisms that link food odors and pheromones to changes in hormone-organized and hormone-activated changes in mammalian behavior, including hormone-driven changes in human behavior. This clarity of my model of adaptive evolution is obviously consistent with what's known about molecular biology when viewed in the context of olfaction and odor receptors, which provide a clear evolutionary trail that can be followed from unicellular organisms to insects to humans.
Lack of clarity and inconsistent results from different model organisms, including mouse models that have been "created" in the lab, attests to missing information about the basic principles of biology and levels of biological organization that enable nutrient-dependent pheromone-controlled adaptive evolution. In some cases, a theory of mutation-caused evolution has been substituted, which appears to make some people think that their derived theories can be compared to a model of nutrient-dependent pheromone controlled adaptive evolution. Their comparisons end when their theory-derived mouse models fail to reproduce human disease in terms of molecular mechanisms of nutrient-dependent epigenesis and pheromone-controlled epistasis.
Kohl, J.V. (2012) Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors. Socioaffective Neuroscience & Psychology, 2: 17338.
February 13, 2013
The problem with this study is that the researchers only investigated one strain of mice (B6), yet generalized their findings to all mouse models of inflammation. After talking with other geneticists, I've written a response to the study that puts it's findings in perspective. http://wp.me/p2Fl7o-8y
February 21, 2013
I am an immunogerontologist. Long time ago, while working as a postdoc at one of the University of Michigan Medical School laboratories I was studying the expression and activity of a calcium-binding protein called sorcin and an enzyme called mu-calpain in murine T cells and foundthem both increasing with advanced age of laboratory mice (the observation on sorcin was reported and published since). Then, after returning home, and becoming more interested in human ageing than in rodents', I have repeated my experiments on human perfipheral blood T cells and found that the relation 'expressio/protein amount/activity and age at least for sorcin was the opposite in humans than in mice (less in the cells from older individuals). Our current study of mu-calpain in human lymphocytes also shows that the murine model cannot be directly applied to ageing of human immune cells, at least not in all facets.