A New Key to Saving Trauma Victims
by Maryann Brinley

There has been a genetic breakthrough in understanding why some individuals recover from trauma while others have life-threatening complications even long afterward.

“What we’ve learned is how elegant nature is in terms of the number of mechanisms that have evolved to allow us to sustain ourselves in response to a trauma or injury,” says Stephen F. Lowry, MD, chair of the Department of Surgery at UMDNJ-Robert Wood Johnson Medical School (RWJMS).

Acute injury, in fact, is by far more lethal than cancer and the leading cause of death and disability in children and productive adults. The mortality rate can exceed 50 percent. To unlock the secrets of individual survival would be a medical milestone as well as a possible life-saver for the three-quarters of a million people who experience sepsis, an immune response which can affect the entire body after a complex traumatic injury. Death from septic shock can occur within hours.

Working with Steve E. Calvano, PhD, RWJMS associate professor of surgery, and collaborators at several national sites, Lowry and the researchers have identified at least 3,700 genes in a network of previously undocumented relationships which are associated with sepsis. Their work was published last October in Nature, “A network-based analysis of systemic inflammation in humans.” Based on the complicated connections in each of these 3,700 genes, the team believes that at least 8,000 other genes may be involved in idiosyncratic ways and at varying time intervals leading up to septic shock. Calvano was the lead author of the paper.

Who survives and who doesn’t could come down to a genetic and biochemical analysis which could alert the medical staff to a patient’s real prognosis. Actual symptoms don’t speak clearly enough. “Some critically injured patients do better in the beginning but have a poor outcome anyway and succumb. Some have a stormy course early on but get better later,” Calvano explains. With this new knowledge about the genomic changes in tissues and white blood cells after an injury, “We may be able to catalogue patients based on the changes in their gene expression” during this sweep of the inflammatory response through the body. “We could predict a patient’s outcome, and tailor clinical care treatment to include new interventions or resuscitation,” based on the cellular signals expressed early.

Reading these clues in gene expression, altered protein production, neuro-endocrine activity and energy at the cellular level could be critical. This study documented the extensive innate immune reaction immediately following an inflammatory challenge, some of which may be helpful for recovery. However, in some people, the balance of pro-inflammatory and anti-inflammatory activity becomes unregulated. In these situations, the normally beneficial immune reaction becomes a cause of severe complications or death.

Calvano points out that this experiment was aimed at measuring genetic expression during periods of inflammation and was not designed to uncover hereditary genetic makeup. Yet, in other ongoing investigations, the team has found evidence that some infectious risk may be inherited as well. And of course, a patient’s existing physical conditions at the time of an injury must also be factored into any clinical trajectory.

The changing science behind the biology of injury is enough to make Lowry pause to recite a line from the poet T. S. Eliot as he recalls the simplicity of earlier thinking. It suits what has happened so nicely: “Where is the wisdom we have lost in knowledge? Where is all the knowledge we have lost in information?”

The story behind this latest discovery about the biology of injury actually began more than 20 years ago in what Lowry refers to as “a little corner of New York City.” The two Steves were working down the research hall from one another at Cornell Medical College, an affiliate of New York Hospital and Memorial Sloan-Kettering Cancer Center. This was before the internet and the dawn of email but collaborative science was just as essential then as it is now. “There is nothing that really supersedes the interaction, exchange of ideas and opportunity to meet. Ideas can come at the strangest times and contexts, and often when you are sitting around the table just shooting the breeze,” Lowry says.

These studies were supported in part as a project with a five-year, multi-institutional award from the National Institute of General Medical Sciences (NIGMS). This so-called “glue grant” brings together researchers from trauma, surgery, genomics, bioinformatics and computer data management to address complex questions in injury biology. “That’s the evolving nature of science these days,” Lowry says. “The beauty of systems biology is to appreciate many previously unrecognized relationships among molecular signals, cells and organ systems.” Their work has been continuously supported by grants from NIGMS since 1982 and Lowry was presented with a $5 million National Institutes of Health (NIH) MERIT award given only to cutting-edge researchers. In 2003, he also received the prestigious Flance-Karl Award from the American Surgical Association in recognition for his contributions to the basic science of surgery and he is one of the most highly cited authors in immunology today.

To understand injury at the sub-cellular level in the experiment cited in the Nature paper, the researchers injected healthy volunteers with a mild bacterial endotoxin and tracked their bodies’ immune response for 24 hours. “The study was
singularly unique because it focused on interpreting the genome-wide response to systemic inflammation in the context of a fully predictable outcome,” Lowry says.

Endotoxins are byproducts of the cell walls of gram-negative bacteria like E. coli. When given in small amounts, they will trigger the immune system to act as if a true infection were present. By themselves, these endotoxins are not particularly harmful. It’s only when the immune system mounts all-out war by flooding the body with an overwhelming amount of inflammatory chemicals that the situation can turn deadly. Lowry himself was one of the first subjects injected with an endotoxin for research purposes in the laboratory many years ago. “The ultimate study of man is man himself, and we wouldn’t do anything to anyone I wouldn’t do to myself.” Calvano also qualifies the safety of their work by adding, “In fact, I believe that endotoxin has been used as a potential immune-stimulating drug in elderly patients.”

These two researchers know how to disagree “constantly,” Lowry says.

“Our differences generally revolve around the fact that Steve Lowry is a big picture kind of guy and I’m more into the methodology and technical side,” Calvano explains. “So we get along pretty well.”

In one of their earliest research projects back in that New York corner, they fed three groups of normal subjects in different ways: one intravenously or parenterally, and another by the normal route through the intestinal tract. The subjects were then administered endotoxin to determine if there were differences in innate immune responses. The intravenous route turned out to predispose a patient to inflammation and organ dysfunction. “I would argue that this is one of the classic studies in the field,” Lowry says. Metabolism has always been a topic near and dear to Lowry’s heart, according to Calvano. “Nutrition is almost a religious principle in managing patients but we are gaining even more appreciation for it in regulating the immune system and the organs in the care of the critically ill,” Lowry says.

In truth, there have been many surprises along their medical research road together but the biggest one may be simply: “How naïve we were once,” Lowry says. “We thought that severe systemic inflammation was initiated and sustained by a limited number of mediators and activated pathways.” Right now, as part of their glue grant work, these new lessons of injury biology are being used to study real trauma and burn patients. “If you look at injury alone in terms of death, disability and economic costs, the statistics are pretty staggering,” Lowry says. He sees the need for insights into the biology of injury so urgently that he admits, “I wake up about 3 a.m. thinking about all that needs to be done.”