Study Reveals Genomics of Inflammation from Severe Injury
Could Improve Prediction of Patient Outcomes, Lead to Tailored
Treatments
When it comes to inflammation, too much of a good thing can be
deadly. In some severely injured patients, this normal healing
process can develop into a lethal, whole-body response, including
bloodstream infection (sepsis) and multiple organ failure. How and
why inflammation turns from healing to harming is still mysterious,
so doctors can't accurately predict how each injured patient will
fare.

To address these issues, scientists have produced the genomic
equivalent of a time-lapse movie, tracking the activity of thousands
of genes through the course of body-wide inflammation. The research
appears in the August 31 advanced online issue of Nature.

"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, Ph.D., director
of the National Institute of General Medical Sciences (NIGMS), the
component of the National Institutes of Health that funded the
research.

The study is the result of a collaborative effort funded by an
NIGMS "glue grant." Glue grants bring together scientists from
diverse fields — in this case surgery, critical care medicine,
genomics, bioinformatics, immunology and computational biology — to
solve major, complex problems in biomedical science that no single
laboratory could address on its own.

To identify all the genes involved in responding to critical injury,
the Inflammation and the Host Response to Injury glue grant team
injected healthy volunteers with bacterial endotoxin. This molecule
causes body-wide inflammation similar to sepsis, with one important
difference — it is well-defined and lasts only 24 hours. By
comparing the changes in gene activity caused by endotoxin exposure
with those caused by trauma, the researchers hope to identify the
molecular markers that spell sepsis.

The research team zeroed in on white blood cells, which help fight
infection and disease and trigger inflammation. The scientists
analyzed the activity of tens of thousands of genes from these
cells, which were taken from the volunteers at regular intervals
over 24 hours. Because this research plots the course of the
inflammatory response over time, it is particularly valuable,
according to Scott D. Somers, Ph.D., NIGMS program director of this
glue grant. "In the case of injury, time is critical. To provide the
best treatment, doctors need to know how the human body responds in
the moments and days after an injury," he said. "No other study of
injury or inflammation has tracked changes to the entire human
genome over time."

The research team found that, of the 5,000 or so genes that
fluctuated in response to endotoxin, more than half were turned
down, causing the blood cells to be less metabolically active. This
seems surprising, as one would expect genes required for healing to
be turned up and for white blood cells to be more, not less, active.
Although other research groups have seen similar genetic results in
animals, scientists don't yet have an explanation for this
counterintuitive response.

Understanding inflammation requires knowing not just which genes are
involved, but how those genes interact with each other. To
investigate this, the group turned to a knowledge base compiled by
Ingenuity Systems, Inc. of Mountain View, Calif., that includes
200,000 published reports on more than 8,000 human, rat and mouse
genes and their genetic interactions. This tool enabled the group to
uncover about 300 genes and several genetic pathways not previously
known to be involved in inflammation.

The Nature article is the second in a planned series of papers that
aim to improve understanding of the human response to injury. In its
first paper, published in March in the Proceedings of the National
Academy of Sciences, the research team described the development of
a microarray technique to analyze the entire genome of white blood
cells from healthy volunteers and critically injured patients. Next,
the team plans to study gene and protein activity in the white blood
cells of a large group of trauma and burn patients over longer
periods of time.

The glue grant team includes scientists from Stanford Genome
Technology Center in Palo Alto, Calif.; University of Medicine and
Dentistry of New Jersey-Robert Wood Johnson Medical School in New
Brunswick, N.J.; Ingenuity Systems, Inc. in Mountain View, Calif.;
University of Florida College of Medicine in Gainesville; Washington
University in St. Louis, Mo.; University of Rochester School of
Medicine in Rochester, N.Y.; and Massachusetts General Hospital,
Harvard Medical School in Boston.

To arrange an interview with Jeremy M. Berg or Scott D. Somers,
contact the NIGMS Office of Communications and Public Liaison at 301-
496-7301. For more information about the Inflammation and the Host
Response to Injury glue grant, see
http://www.nigms.nih.gov/news/releases/tompkins.html and
http://www.gluegrant.org/. For general information on glue grants,
go to http://www.nigms.nih.gov/funding/gluegrants.html.

NIGMS (http://www.nigms.nih.gov), a component of the National
Institutes of Health, supports basic biomedical research that is the
foundation for advances in disease diagnosis, treatment, and
prevention.

The National Institutes of Health (NIH) — The Nation's Medical
Research Agency — includes 27 Institutes and Centers and is a
component of the U. S. Department of Health and Human Services. It
is the primary Federal agency for conducting and supporting basic,
clinical, and translational medical research, and investigates the
causes, treatments, and cures for both common and rare diseases. For
more information about NIH and its programs, visit
http://www.nih.gov.

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