For decades, mice have been the species of choice in the study of human diseases. But now, researchers report stunning evidence that the mouse model has been misleading for at least three major killers -- sepsis, burns and trauma. As a result, years and billions of dollars have been wasted following false leads, they say.
The study does not mean that mice are useless models for all human diseases. But it does raise troubling questions, its authors said, about diseases such as the ones in the study that involve the immune system, including cancer and heart disease.
"Our article raises at least the possibility that a parallel situation may be present," said H. Shaw Warren, a Massachusetts General Hospital sepsis researcher and lead author of the new study.
The paper, published Monday in the Proceedings of the National Academy of Sciences, helps explain why every one of nearly 150 drugs tested at huge expense in patients with sepsis has failed. The drug tests all were based on studies in mice. And mice, it turns out, have a disease that looks like sepsis in humans but is very different from the human disease.
Medical experts not associated with the study said the findings should change the course of research worldwide for a deadly and frustrating disorder. Sepsis afflicts 750,000 patients a year in the United States, kills a quarter to half of them and costs the nation $17 billion a year. It is the leading cause of death in intensive-care units.
"This is a game changer," sepsis expert Mitchell Fink at the University of California, Los Angeles, said of the new study.
Potentially deadly immune responses occur when a person's immune system responds 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 Clifford Deutschman, who directs University of Pennsylvania sepsis research and was not part of the study.
The ramped-up immune system releases its own proteins in such overwhelming amounts that they make capillaries 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 nation, began by studying white blood cells from hundreds of patients with severe burns, trauma or sepsis to see what genes are being used by white blood cells when responding to these danger signals.
The researchers found some interesting patterns and accumulated a large, rigorously collected data set that should help move the field forward, said Stanford University genomics expert Ronald Davis, another lead author of the new paper. Some patterns seemed to predict who would survive and who would end up in intensive care, clinging to life and, often, dying.
The group had tried to publish its findings in several papers. One objection, Mr. Davis said, was that the researchers had not shown the same gene response had happened in mice. "They were so used to doing mouse studies that they thought that was how you validate things," he said. "They are so ingrained in trying to cure mice that they forget we are trying to cure humans. That started us thinking: Is it the same in the mouse, or not?"
The group decided to look, expecting to find some similarities. But when the data were analyzed, there were none at all. "We were kind of blown away," Mr. Davis said.
The drug failures became clear. For example, often in mice, a gene would be used, while in humans, the comparable gene would be suppressed. A drug that works in mice by disabling that gene could make the response even more deadly in humans.
Even more surprising, Dr. Warren said, was that different conditions in mice -- burns, trauma, sepsis -- did not fit the same pattern. Each condition used different groups of genes. In humans, though, similar genes were used in all three conditions. That means, Dr. Warren said, that if researchers can find a drug that works for one of those conditions in people, the same drug might work for all three.
The study's investigators tried for more than a year to publish their paper showing 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.
Science and Nature said it was their policy not to comment on the fate of a rejected paper, or whether it had even been submitted to them. But, Ginger Pinholster of Science said, the journal accepts only about 7 percent of the nearly 13,000 papers submitted each year, so it is not uncommon for a paper to make the rounds.