Room for improvement in mouse models, UF surgical investigators say

UF researchers co-authored two recently published journal articles that may reform scientists’ use of a staple in medical research: the mouse model.

One article describes a series of studies by researchers from 16 different institutions that examined genomic, responses to several serious health threats in mice and in people. What they found sheds new light on the decades-old method of using mice to investigate health conditions that affect people, and possible treatments for those conditions. The journal Proceedings of the National Academy of Sciences published the study electronically in February.

“The data suggests that if you look at the gene level between a mouse and a man in response to trauma or burns, that the genomic response is really very dissimilar,” said Lyle Moldawer, Ph.D., a co-author of the article and a UF professor of surgery. “They looked at the individual genes that changed and [how they changed] and they found that on that sort of analysis, it was really quite poor.”

Many human diseases involve inflammation and it is a cornerstone of conditions such as sepsis, a type of systemic infection that can shut down organs. Each year, sepsis and related conditions keep hundreds of thousands of trauma and acute care patients in the U.S. from recovering fully. The authors said their findings help explain why nearly 150 clinical trials of potential drugs meant to tame sepsis and other inflammation-based problems in people all failed, despite promising results in preliminary tests using mice.

“If you’re looking at specific therapies that target individual genes, then the mouse isn’t a good model for that,” Moldawer said.

However, mice can still be useful in studying inflammation and its causes and effects. In fact, studies of mice have proven notably important in the development of drugs for rheumatoid arthritis, inflammatory bowel disease and psoriasis, as well as for autoimmune diseases like type I diabetes and lupus. Moldawer said trauma and burns cause inflammation and predictable immune system responses in both mice and people, though the species achieve these results through expression of different genes.

A separate article published online in February by the journal Critical Care Medicine showed that in studies of trauma, the severity of a mouse’s injury affects its systemic response.

Based on that finding, researchers have developed a new model designed to better mimic human responses to trauma and inflammation at the genomic level.

Most mice used for studying inflammation and sepsis have just one severe injury, said Philip Efron, M.D., a co-author of the article and an assistant professor of surgery and anesthesiology at UF. He called these mice the “old model,” and cited the recently published Proceedings of the National Academy of Sciences article describing the lack of genomic similarity between their responses to trauma and humans’.

“The old model used to do a pretty good job in the very early acute phase,” he explained, referring to the time immediately after a traumatic injury takes place.

What that model doesn’t mimic well are the later phases, when humans struggle and fight to recover. With advances in trauma care, most patients survive the first phase to face great systemic challenges later.

Efron said he hopes the team’s new mouse model will spread, helping investigators to improve their work involving mice.

“We’ve published it and we’ve made it available and hopefully people will start using it,” he said. “We have had some requests from other institutions to try to learn how to go about it.”