Genome analysis has applications across the entire spectrum of drug discovery and development, including discovery of genes linked to disease/drug targets, development of DNA-based clinical diagnostics and pharmacogenomic analysis.
It is set to provide a means for identifying pathways that are critical to disease, and discovering target effects of compounds. By combining data that interpret changes in genes, proteins, metabolites, it can provide a means of diagnosis and evaluating drugs that alter disease outcome.
The researchers demonstrated that these state-of-the-art techniques produced useful insights into the health of critically ill patients. Despite significant advances in organ support technology, physicians' ability to predict whether or not a given patient will respond to a course of treatment has been poor.
"It's an exciting time because our field has experienced frustration with some of these questions, many of which have important ramifications for how we treat patients," says J. Perren Cobb, the paper's lead author.
The findings, which are available online and will be published in the March 29 issue of the Proceedings of the National Academy of Sciences, makes it possible for physicians to begin answering questions about critical care through genomic analysis.
The new study, conducted by Cobb and colleagues at the Washington University School of Medicine, asked whether the technology could detect differences in the activity levels of genes in critically ill patients versus healthy patients.
"We wanted to make sure that we could consistently get the same results from an analysis regardless of where the sample was gathered," Cobb said.
Researchers applied DNA microarrays, to blood samples and skeletal muscle from 34 severely injured patients and 23 healthy individuals. Scientists identified aspects of microarray testing procedures that were vital to obtaining results that could be reproduced regardless of where the studies were conducted.
They also showed that genetic analysis technology achieved sensitivity and resolution sufficient to "see" changes in gene activity levels that take place in cells in the critically ill. These changes in gene activity can reprogram white blood cells, immune system cells that circulate in the bloodstream.
This reprogramming alters the relative populations of the different types of white blood cells and the genes they express. One white blood cell, the neutrophil, normally makes up 40 to 60 per cent of circulating white blood cells but rises to comprise 80 to 90 per cent after critical injury. The new approach will allow the investigators for the first time to monitor neutrophil gene activity genome-wide in injured patients.
In the new era of genetically based critical care research, one focus will be developing a better understanding of how these cells and other factors control inflammatory responses to severe injury.
"It has been clear for approximately two decades that critical injury can trigger the release of immune factors that cause massive inflammation, and this can sometimes overwhelm the body's ability to cope," Cobb said.
"We have produced a great deal of insight into how those inflammatory responses are generated, and we've tried a number of strategies to block or weaken them, but so far we've had relatively little success."
As scientists understand how multiple genes interact to produce inflammatory responses becomes more complete, they may be able to develop more effective ways to dampen those responses and save lives.