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Genes may help explain who survives trauma

/ Source: The Associated Press

Surviving major trauma — a car crash, gunshot wounds, burns — isn’t just a matter of fixing the obvious injuries. About a week into the healing, many patients’ organs suddenly fail, as doctors watch helplessly.

They can’t predict who will go into this downward spiral, or how victims will fare. Numerous attempts at treatments have failed.

Now a massive federal research program is under way to determine why one patient dies while another with equally severe injuries lives. And the first good clues suggest that traumatic injury can literally change people’s genes in a way that makes their immune systems run amok, harming their own organs.

If the finding holds up, in gene tests in emergency rooms around the country, it could do more than help doctors tell in advance which of their patients is most likely to live. Organ failure causes about a quarter of the nation’s 160,000 trauma-related deaths each year, and the ultimate goal is to finally find a way to treat or even prevent it.

“Right now, almost all the therapies in the ICU are supportive. The patient’s basically dependent on fixing themselves,” says Dr. Paul Bankey, trauma chief at the University of Rochester Medical Center.

“Whether they’re going to ultimately make it or not boils down to whether they acquire organ failure.”

Leading killer of young people

Trauma is the leading killer of Americans under age 45, mostly because of car crashes, and the nation’s No. 5 killer overall.

People with injuries that once were invariably fatal today have hope of surviving thanks to increasingly skilled first-responders and advances in emergency-room care.

But once the injuries themselves are stabilized — doctors have done all they can, and sent the patient to the intensive care unit to heal — progress hits a wall. Survival hasn’t improved much in a decade, and doctors realized it was because how the body overreacts to an injury can cause even more damage than the initial trauma.

The question is why, and what to do about it. So the National Institutes of Health funded almost two dozen leading trauma hospitals to figure that out, in a $67 million project known as a “glue grant” because it brings together fields where researchers don’t usually collaborate.

First, the team discovered that even state-of-the-art trauma centers don’t agree on exactly how to care for their patients, and had to write guidelines for best practices. When the glue-grant hospitals adopted those guidelines, they saw deaths from trauma drop, says project chief Dr. Ronald Tompkins, a Harvard professor who heads the burn service at Massachusetts General Hospital.

Among the lessons learned: Giving too many blood transfusions can do more harm than good. Rather than helping more oxygen circulate in their bodies, the transfusions suppressed patients’ overall immune systems.

Then it was time for the project’s real work: Studying the genes of trauma victims to see, at biology’s most basic level, why some fare better than others.

Several hundred genes involved

Last month, research led by Rochester immunologist Carol Miller-Graziano uncovered a surprise: She compared blood from 18 trauma victims in the midst of organ failure with 22 healthy people, and found that severe injuries seemed to trigger a pattern of changes in several hundred genes.

Those changes, in turn, seem to shut down crucial immune cells known as T cells before they can finish their job, researchers reported in the journal Proceedings of the National Academy of Sciences.

The immune system performs a balancing act believed rooted in evolution. First comes inflammation, as primitive white blood cells swarm to an injury site, emitting various chemicals to destroy any nearby bacteria and thereby prevent infection. Inflammation works well for small injuries, the only kind ancient humans could have survived.

But those cells aren’t very specific, meaning they can harm nearby healthy tissue, too. More targeted immune cells, such as T cells, are supposed to help, armed with a quality-control mechanism, to end the immune attack once the job is done.

If injuries end that second step too early, inflammation can run out of control until the lungs and other organs are damaged. Tompkins calls it an evolutionary snag.

“We are now seeing features that allowed ancient man to survive, and we’re seeing those features now in massive injuries in our intensive care units,” he explains. “The selection process that led to those responses were designed for small injuries. They’re certainly not designed for wrapping your BMW around a tree trunk.”

Next, the glue-grant researchers must prove whether the newly found gene changes really do play a role in organ failure. If so, the finding has implications beyond treating trauma victims — because inflammation plays a role in a host of illnesses, from heart disease to cancer.