Study Shows Why Mice Don’t Make It for Researching Some Life-Threatening Conditions

Mice are unwelcome residents of your cupboard, but they are popular residents of medical labs that use them as surrogates for humans in conducting disease research. Recent developments, however, have demonstrated that for at least three major health problems, the tiny rodents are not good subjects from which to draw conclusions about human treatments.

The study, published in Proceedings of the National Academy of Sciences (PNAS), calls into question decades of time and billions of dollars spent on research using the mouse model to study human health problems, particularly sepsis (bloodstream infection), burns and trauma. Mice still might be suitable human substitutes to study other disorders, but probably not for those involving the immune response to health threats.

As recounted in a story in the New York Times, the study helps explain why every one of nearly 150 drugs that were developed based on mice studies failed when given to patients with sepsis. Mice can contract something that looks like sepsis in humans, but it’s not the same.

Sepsis, which strikes 750,000 people every year in the U.S., is a symptom of the body trying to fight infection, and it can be fatal; one-quarter to one-half of sepsis patients die, and the cost, says The Times, is $17 billion a year. Sepsis is the leading cause of death in intensive care units.

As The Times explains, potentially deadly immune responses occur when someone’s immune system overreacts to perceived danger, such as toxic bacteria, viruses, fungi or proteins released from cells damaged by trauma or burns.

The system releases so much of its own proteins that capillaries leak, and serum seeps out of the tiny blood vessels. Blood pressure falls, and vital organs don’t get enough blood. If the infection-and the leaking-isn’t stopped, tissue is damaged and vital organs eventually fail.

The medical community responded to the new research by saying that the findings should change the course of sepsis research worldwide. “This is a game changer,” Dr. Mitchell Fink, a sepsis expert at the University of California, Los Angeles, told The Times.

The study took 10 years and involved 39 researchers. They studied 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 those health threats.

The researchers defined patterns that seemed to predict who would survive and who would end up in intensive care. They tried to publish their findings several times, but got rejected by reviewers. One objection was because they hadn’t shown the same gene response had happened in mice, which is the traditional way such studies are validated.

That got them thinking, The Times reports, that maybe the response isn’t the same in mice. So they looked for it and were surprised not to find any similarities in the data they analyzed.

That makes the drug failures clear–often in mice, a gene would be used when the comparable human gene would be suppressed. “A drug that worked in mice by disabling that gene,” The Times explains, “could make the response even more deadly in humans.”

Burns, trauma and sepsis in mice did not share a pattern. Each condition used different genes. But in humans, similar genes were used in all three conditions. So if researchers can find a drug that works for one of those conditions in people, it might work for all three.

The researchers tried for more than a year to publish the paper that showed no relationship between the genetic responses of mice and those of humans. One journal that rejected it told The Times that it accepts only about 7 in 100 of the nearly 13,000 papers submitted each year. So it’s not uncommon for a paper to make the rounds.

Even this one? With our culture’s penchant for making everything a “legend,” with the media frequently too lazy to carefully examine scientific research in favor of bold, if shallow, headlines, rarely is the term “groundbreaking study” used accurately.

But this time it could be.

Instead of the journals rejecting the paper because it contained scientific errors, “the most common response was, ‘It has to be wrong. I don’t know why it is wrong, but it has to be wrong,'” according to one Times source.

When the PNAS reviewers read the paper, The Times reports, they were stunned by just how bad the mouse data are. “It’s really amazing – no correlation at all,” Fink told The Times. Until now, he said, “to get funding, you had to propose experiments using the mouse model.”

But one fact makes you wonder why the research community couldn’t see the forest for the trees: It’s difficult to kill a mouse with a bacterial infection. As The Times says, mice need a million times more bacteria in their blood than what would kill a person.

“Mice can eat garbage and food that is lying around and is rotten,” one of the study’s authors told The Times “Humans can’t do that. We are too sensitive.”

If we knew why mice were so resistant, maybe we could figure out how to make people resistant. And now, that means human biology, not mouse biology, is the raw material for discovery.

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