Scientists Get Look At Genes' Defensive Playbook; Study Tracks Human Genomic Response To Inflammation

The body's overwhelming genetic defense, which has implications forthe survival of patients who are severely burned or injured, wasrevealed in a sweeping analysis of gene activity in volunteers who wereinjected with a bacterial product that temporarily created flu-likesymptoms.

"During a 24-hour period, the expression of more than 3,700genes changed in blood leukocytes," said Lyle Moldawer, Ph.D., asurgery professor in the University of Florida College of Medicine,part of the national consortium that published the findings. "It was adramatic reprioritization of genes. But beyond individual genes, wewere able to look at networks, or functional modules of different geneclusters, that change in concordance with one another. We have nowidentified previously unknown relationships among different genes thattell us in greater detail how blood cells respond to an infectiouschallenge."

Inflammation is part of normal healing when people are severelyburned or injured, but in some patients, it can be fatal, causingbloodstream infections and multiple organ failure. Learning how and whyinflammation becomes harmful will help doctors more accurately predicthow each injured patient will fare.

"This work represents a major step in understandinginflammation in severely injured or burned patients," said Jeremy M.Berg, Ph.D., director of the National Institute of General MedicalSciences, the component of the National Institutes of Health thatfunded the research. "We hope this knowledge eventually will helpphysicians better predict patient outcomes and tailor treatmentsaccordingly."

UF Genetics Institute researchers are part of a national groupof scientists united by a five-year, $37 million "glue grant" from theNIGMS. Glue grants bring together scientists from diverse fields -- inthis case surgery, critical care medicine, genomics, bioinformatics,immunology and computational biology -- to solve problems in biomedicalscience that no single laboratory could address.

Scientists injected healthy volunteers with a microbialproduct that temporarily causes nausea and fever, triggering naturalimmune responses. The condition is similar to sepsis, which can happenwhen the body's infection-fighting white blood cells spring intoaction, causing potentially harmful inflammation in the process.

"Basically we made the volunteers appear septic for a couple ofhours and examined changes in the gene expression from their whiteblood cells," Moldawer said. "Such genomic analyses give us the abilityto simultaneously survey the activity of every gene in the cell, givingus vast lists of genes that change in response to stimulation. Itprovides us with an unprecedented amount of data."

To make sense of the enormous amount of information,researchers plugged their list of nearly 4,000 gene changes into adatabase of interactions of known human and mouse genes developed byIngenuity Systems Inc. of Mountain View, Calif. The results identifiedthe networks of genes that helped the body respond to the challenge.

"We were able to identify changes in functions that we neverwould have seen before," Moldawer said. "For example, the ability ofthe infection-fighting cells to make energy appeared to bedown-regulated, as if the cells were shutting down all other functionsnot required to rid the body of the bacteria. This may well be thesignal that something is wrong with the cell and may be a reason whysome patients who are injured or infected go on to develop organfailure."

With that knowledge, scientists may be able to look at new waysto re-establish stability within the cells and avert the negativeconsequences of infection fighting.

"The apparent repression of genes that occurs has never beenfully appreciated," said Henry Baker, Ph.D., associate director of theUF Genetics Institute and director of the UF lab that performs genomicanalyses for the consortium. "Initially, more than half of the genesbecame less active, but over the long haul, they were more focused onthe inflammatory response. By drawing samples for analysis over sixtime points in 24 hours, we were able to infer the sequence of eventsand how some changes in gene expression cause other changes."

Additional genomic analysis took place at the Stanford GenomeTechnology Center in Palo Alto, Calif., and the department of surgeryat Washington University in St. Louis, Mo.

The research is particularly valuable because it plotsinflammatory response over time, according to Scott D. Somers, Ph.D.,NIGMS program director of this glue grant.

"In the case of injury, time is critical," Somers said. "Toprovide the best treatment, doctors need to know how the human bodyresponds in the moments and days after an injury. No other study ofinjury or inflammation has tracked changes to the entire human genomeover time."

The glue grant team includes scientists from the UF College ofMedicine; Stanford; Washington University; the University of Medicineand Dentistry of New Jersey-Robert Wood Johnson Medical School in NewBrunswick, N.J.; Ingenuity Systems Inc.; the University of RochesterSchool of Medicine in Rochester, N.Y.; and Massachusetts GeneralHospital, Harvard Medical School in Boston.