Years of research into inflammatory disease, costing billions of dollars in research funding, has been wasted on the lowly mouse.
Two years ago, McGill University researcher Jeffrey Mogil used a similar approach to compare changes in gene expression across models of chronic pain. But instead of comparing mice and humans, or other rodents and primates, Mogil looked at a pair of common lab animals that appear to be quite similar: rats and mice. Not long after that paper was published, Mogil told me that the results had "scared the hell" out of him: The gene profiles from mice and rats were nothing alike. In fact, they were as distinct from one another as the mouse and human profiles described in this week's study.
All these details notwithstanding, years of practice and refinement have made the modern lab mouse the most powerful tool we have in research medicine. Scientists all over the world run experiments and develop methods using the same, standard organism. That's why a mouse can be bought and bred for a fraction of the cost of other animals, why it can have its genes knocked in or out or turned on and off throughout its life, why it's been the subject of a million research papers and will be the subject of a million more. No model organism provides more depth and flexibility. None is as brilliantly efficient.
The authors of this week's study know all this—they call the mouse "a cornerstone of modern biomedical research," and make it clear that they have no interest in abandoning the standard model even in their modest field of inflammation. Instead, they'd like to "raise the bar" for mouse studies aimed at curing human disease by asking colleagues to show, first of all, that whichever gene or molecule turns up in animals applies to humans, too. This vital step has been ignored for far too long, as scientists relied instead on the simple and not-so-enlightening measure of mouse survival. Asking whether a mouse is alive or dead—whether it's "paws-up or paws-down," as they say—may be a good way to start an experiment, but it's a terrible way to finish one.
There's another way to look at all the difference data, though. The fact that mice are so unlike people could be the thing that makes them interesting. One might be inclined to ask what makes the mice so unusually impervious to inflammation. If we stopped treating them as a lousy model of ourselves and studied them instead for the special talents that are all their own, perhaps we'd find out something new. It's the same logic that drives the study of the naked mole rat, which has an amazing ability to shrug off carcinogens, or the Burmese python, which can sustain a swollen heart.
But to call the mouse exceptional, and not treat it as a furry stand-in for ourselves—i.e., to focus on the differences across the animal kingdom as much as on the similarities—would require a radical shift in how we do science. For now, it remains an open secret in biomedicine that mouse models can be a lousy fit, and that no matter how nimble or sophisticated our tools of analysis might become, science still gets mired in the kludgy move from one species to another.
The PNAS paper shows how hard it will be to negotiate this major problem of translation. It took the authors a decade of data collection and analysis and tens of millions of dollars in federal money to finish their experiment. The huge collaboration that produced the inflammation data set up what they called a "model validation core"—a group of laboratories that hoped to figure out "whether experimental models of tissue injury, blood loss, and endotoxemia resemble the human inflammatory response to injury using state of the art genetic and analytical assays." But this was just one small part of a much bigger project, tucked into a "glue grant" from the National Institute of General Medical Sciences.
The sad fact is that funders favor projects that will deliver positive results—new genes, new pathways, new drug targets—not downer news about what we might be doing wrong. A bias works against this research at the other end of science, too, once the data has been collected and the conclusions spelled out in black and white. Writing in the New York Times, Gina Kolata notes that the study's authors spent a year just trying to publish the paper. It was rejected from the top two journals, Science and Nature, and the authors fell back to PNAS because a personal connection there eased the process of peer review. Indeed, the same mouse-inclined researchers who serve on federal grant-review committees—sometimes called the "mouse mafia" (as opposed to, say, the "monkey mafia")—also work for the editorial boards of science journals.
The story of how the PNAS study was conceived and published suggests that we're not yet on the eve of a Great Mouse Reckoning. Even if money for similar research in other fields of biomedicine were forthcoming, the science itself might be impractical. It's easy enough to take white blood cells from hospital patients for a large-scale genetic study of inflammation, but what if the disease you're looking at involves the heart or brain instead of plasma? Chronic pain, for example, affects more than 30 percent of the population, but to study this group of patients in the same way as researchers did for the victims of acute inflammation would require a far more invasive set of procedures. "The 'relevant' tissues (i.e. spinal cord, thalamus, cortex) tend to be ones that humans are not eager to donate," Mogil explains.
In 2011, I argued that any standard organism has a natural limit to its utility, and that we may have reached that point already with mice. If that's the case, we'll need to start with something new—a more comparative, organic form of science, perhaps, one based on differences across animals instead of similarities between them. But we'll never know if it's time to make this major change unless we do the sort of tricky, trying work that was published earlier this week. Have our mouse models finally run their course—not just in the study of inflammation but for cancer, tuberculosis, stroke, and all other killer diseases? It's time to find out.