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Release: Feb. 19, 2002

NOTE TO EDITORS: For a copy of the research article mentioned in this release, contact the Proceedings of the National Academy of Sciences news office at (202) 334-2679 or pnasnews@nas.edu or visit http://www.eurekalert.org/.

UI researchers find additional genes that may code for body's natural antibiotics

IOWA CITY, Iowa -- To defend against everyday encounters with bacteria, the human body's immune system produces a shield of natural peptide and protein antibiotics. Beta-defensin genes are known to code for one class of these antimicrobial peptides. Yet only five beta-defensin genes previously were identified in the human genome.

Using a completely computer-based search strategy, investigators in the UI Colleges of Medicine and Engineering have found 28 additional human beta-defensin genes, bringing the total to 33. The findings, which could have implications for understanding the underlying molecular defects that cause cystic fibrosis, appear in the Feb. 19 issue of the Proceedings of the National Academy of Sciences.

Additional research is needed to determine whether the newly discovered beta-defensin genes actually code for antimicrobial peptides, said Paul McCray, M.D., UI professor of pediatrics and the study's corresponding author and principal investigator. He and co-principal investigator, Brian Schutte, Ph.D., UI assistant professor of pediatrics, will want to learn where the peptides are made in the body and what organisms they kill.

"Our main goal now is to figure out which members in this new set of beta-defensin family members are important for protecting the lungs against infection," McCray said. "Then we can think about how that protection process might be altered in cystic fibrosis and consider interventions."

The possibility of additional infection-fighters in the lungs might add to understanding of the chronic lung infections in people with cystic fibrosis. The disease alters the normal defenses of the lung-lining surface. One way this happens is by making antimicrobials less effective. The resulting bacterial infections cause an overactive immune response that leads to inflammation and tissue damage.

While additional research lies ahead, the path to finding the beta-defensin genes required an interdisciplinary effort involving the UI College of Medicine and the UI College of Engineering. The team used an innovative combination of two computer search programs, BLAST and HMMER.

When the research team started their project two years ago, only five beta-defensin genes were known. "We thought there were more," Schutte said. "These beta-defensin genes are very small and hard to find using a single search method. We hypothesized that if we could get more of the sequence from the human genome and scan it in new ways, we would find additional beta-defensin genes."

With that idea, the researchers turned to Thomas Casavant, Ph.D., UI professor of electrical and computer engineering. He suggested they use the HMMER software (based on a mathematical technique employing Hidden Markov models), along with the more traditional BLAST software, and apply the tool to the entire genome -- some three billion base pairs of DNA.

Using HMMER to scan the entire genome normally requires 48 hours of processing time on a single high-performance computer workstation. However, by using a technique that employs 32 processors in a "cluster" computer, this time was reduced to about three hours.

"Each time we did these reiterations with HMMER and BLAST, we refined the model," Casavant said.

Casavant explained that BLAST uses one model sequence to look for similarities, whereas HMMER takes all the sequences already documented and uses them to find comparable sequences. He compared the use of the two tools to a complimentary search for members of the Osmond family, as an example.

"Using BLAST is like taking a picture of just one of the Osmonds and then looking for other people who look like that individual," Casavant said. "Using HMMER is like taking a family portrait of the Osmonds and using the ensemble to look for people who look similar."

"Using BLAST and HMMER together turns out to be much better than using either one of them alone," added McCray.

Several UI students played essential roles in the time-intensive programming and analysis, including Jesse Walters, an undergraduate in electrical and computer engineering; Joseph Mitros, who initially participated in the research through the Interdisciplinary Summer Undergraduate Research Program and now is a research assistant in pediatrics; and Jennifer Bartlett, a student in the Genetics Ph.D. Program.

"The students were key," McCray said. "Their seats were firmly attached to the chairs in front of their computers."

Other UI contributors included Hong Peng Jia, M.D., a research scientist in pediatrics; and Michael J. Welsh, M.D., the Roy J. Carver Chair in Physiology and Biophysics, UI professor of internal medicine and physiology and biophysics, and a Howard Hughes Medical Institute investigator.

The study was funded in part by grants from the National Heart, Lung, and Blood Institute and the National Institute of Child Health and Human Development, both part of the National Institutes of Health, and from the Howard Hughes Medical Institute. Casavant also received a Cystic Fibrosis Genome Analysis Grant.

Information about McCray's and Casavant's laboratories is available online at, respectively: http://mccraylab.genetics.uiowa.edu/ and http://genome.uiowa.edu/. In addition, information about

Welsh's cystic fibrosis research is at the following Howard Hughes Medical Institute Web site: http://www.hhmi.org/research/investigators/welsh.html.

For information about cystic fibrosis, visit the Cystic Fibrosis Foundation online at http://www.cff.org/

University of Iowa Health Care describes the partnership between the UI College of Medicine and the UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at http://www.uihealthcare.com/.