Powerful Technologies Probe Innate Immunity

WASHINGTON -- A comprehensive and detailed picture of innate immunity - the human body's first line of defense against disease - is the goal of scientists funded by a recently awarded five-year, $24-million grant from the National Institute of Allergy and Infectious Diseases (NIAID).

Researchers at The Scripps Research Institute (TSRI) in La Jolla, Calif., the Institute for Systems Biology (ISB) in Seattle, and Rockefeller University in New York are using techniques that straddle the divide between biology and information science to fathom the workings of innate immunity. Knowledge generated could help scientists develop treatments for septic shock, certain autoimmune disorders and diseases caused by potential agents of bioterrorism.

Daniel Rotrosen, MD, director of NIAID's Division of Allergy, Immunology and Transplantation, notes, "The collaborators at TSRI, ISB and Rockefeller University have complementary expertise that is most impressive."

"Our goal is to develop an encyclopedia of innate immune system activity," says Richard J. Ulevitch, PhD, head of TSRI's immunology department and the project's principal investigator.

As its name indicates, innate immunity is inborn and provides an all-purpose defense against invasion. Innate immune system cells, including certain skin cells called Langerhans cells, arrive soon after foreign elements are detected. Some system components, called macrophages, find and engulf microorganisms, while others release chemicals that kill the organism directly. Still other cells begin recruiting specialized immune cells to the region.

Ulevitch and his co-investigators face a daunting task - identifying the thousands of genetic changes, proteins generated and biochemical pathways triggered by encounters between innate immune system cells and infectious agents. Unlike the highly specific antibodies, which are produced in almost infinite variety and which match a particular disease organism like a key in a lock, cells of the innate immune system react generically to a wide range of substances, including molecules found in the cell walls of many kinds of bacteria.

An encyclopedic account of these complex and interwoven processes requires a systems biology approach, says Ulevitch. Dubbed "21st-century biology," the relatively new field of systems biology melds mathematics, computer modeling, and new techniques of gene and protein analysis in an effort to gain a wide-angle view of biological systems.

Unlike traditional, hypothesis-driven biology in which a single gene or protein is selected for study based on its proposed function, systems biology assembles information about many genes, proteins and biochemical reactions at once without regard for function. These enormous amounts of data are then integrated and examined from multiple perspectives to learn how the system as a whole behaves.

Scientists at TSRI, ISB and Rockefeller University will focus on human innate immune system genes that are turned either off or on when a cell meets an infectious organism. Due to the high degree of similarity in the innate immune systems in all animals, the scientists can employ mice to quickly determine which gene groups deserve further exploration. Both the human and mouse genes, for example, encode proteins involved in inflammation, a generic first response to invasion by foreign organisms or to trauma. Uncontrolled inflammation can cause extensive cell damage and even death. Better understanding of proteins involved in the initiation and control of inflammation could help scientists find targets for new drugs that can precisely modify the inflammatory response.

NIAID also recently awarded two contracts to support research in a key area of systems biology, bioinformatics. Bioinformatics is the computational analysis and organization of biological data such as gene sequences and protein structure. The contract awardees, Research Triangle Institute in Research Triangle Park, N.C., and Northrop Grumman in Herndon, Va., will first assess the bioinformatics needs of scientists working in such areas as transplant biology and autoimmune diseases. The contractors will also develop and test a prototype system that reliably and simply collects, stores and analyzes many forms of biological data generated by multiple laboratories.

"The new grant, along with these new bioinformatics contracts, signals NIAID's interest in advancing bioinformatics resources to support both basic and clinical research on immune-mediated diseases," NIAID's Rotrosen notes.