Study provides first steps toward individualized treatment of serious injuries

A multi-institutional research collaborative has begun to decipher the complex interplay of genes that underlies the body's response to major injuries.

In a report to appear in the journal Nature, researchers from the Inflammation and Host Response to Injury program describe their investigation into how the process of systemic inflammation - an immune response which affects the entire body - alters the expression of genes within white blood cells. The findings are a first step towards the overall goal of understanding why some individuals recover well from traumatic injuries while others can have dangerous inflammatory complications that may develop long after the original injury.

"Some of the most serious problems facing patients with major burns or trauma result from out-of-control inflammation, a process we still do not understand well," says Ronald Tompkins, MD, Sc.D., chief of the Burns Service at Massachusetts General Hospital (MGH) and national leader of the project. "By looking at how people respond to injury on a genomic and proteomic level, we hope someday to be able to tailor treatments to patients' individual needs and keep the inflammatory response from doing more harm than good."

The project is supported by the National Institute of General Medical Sciences (NIGMS) through what are called "glue grants," so named because they bring together researchers from different institutions and across several fields - for example trauma medicine, genomics, bioinformatics and computers - to address complex scientific problems. The inflammation team incorporates scientists from 22 research centers who have been working together for four years.

The Nature paper, which is receiving early online release, describes one of the group's initial experiments, led by researchers from the Robert Wood Johnson Medical School at the University of Medicine and Dentistry of New Jersey and the Stanford Genome Technology Center. To examine the physiologic mechanism behind systemic inflammation, healthy volunteers were injected with bacterial endotoxin, which produces a widespread but controlled inflammatory response that subsides quickly. Blood samples were taken at several points after participants received endotoxin, and the expression levels of genes in circulating white blood cells were analyzed and compared with those of control participants using technologies that tested almost 45,000 probes, representing more than 30,000 possible human genes.

The researchers found that expression levels of more than 3,700 genes in white blood cells changed significantly during the hours after endotoxin administration, while gene expression in control participants was unchanged. More than half the identified genes were expressed at lower levels, including several genes involved in the function of mitochondria - subcellular structures that produce the cells' energy - suggesting reduced activity of these key immune cells.

Since each gene can interact with many others in complex patterns, the researchers turned to a database of information on thousands of human, mouse and rats genes, compiled from more than 200,000 scientific articles with technology developed by Ingenuity Systems Inc. Using that tool they were able to construct inflammation-associated molecular networks involving interactions between more than 8,000 genes. Hundreds of these genes and pathways were not previously known to be associated with the inflammatory process.

"Not only has this work identified novel pathways of inflammation, it also demonstrates an approach to getting more meaning out of the data provided by microarray gene expression profiles. We're hoping to determine what tools are going to be most effective in producing real knowledge from these lists of perturbed genes," says Tompkins, who is the John Francis Burke Professor of Surgery at Harvard Medical School.

"This work represents a major step in understanding inflammation in severely injured or burned patients. We hope this knowledge eventually will help physicians better predict patient outcomes and tailor treatments accordingly," said Jeremy M. Berg, PhD, director of the NIGMS, one of the National Institutes of Health.

The senior authors of the Nature paper are Stephen Lowry, MD, chair of Surgery at Robert Wood Johnson Medical School (RWJMS), and Ronald Davis, PhD, professor of Biochemistry and Genetics and director of the Stanford Genome Technology Center (SGTC). The lead authors are Steve Calvano, PhD, RWJMS, and Wenzhong Xiao, PhD, SGTC; co-authors are Daniel Richards, Ramon Felciano, PhD, Raymond Cho, and Richard Chen of Ingenuity Systems Inc.; Henry Baker, PhD, Kevin Tschoeke, MD, and Lyle Moldawer, PhD, University of Florida; Bernard Brownstein, PhD, and Perren Cobb, MD, Washington University School of Medicine; Carol Miller-Graziano, PhD, University of Rochester School of Medicine; and Michael Mindrinos, PhD, SGTC.

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