Lab receives NIH grant to fight tuberculosis

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LOS ALAMOS, N.M., Sept. 26, 2000 -- A six-nation consortium of 13 institutions led by the Department of Energy's Los Alamos National Laboratory will perform research that someday may help eradicate tuberculosis under a recent multimillion dollar grant from the National Institutes of Health.

NIH's National Institute of General Medical Sciences and National Institute of Allergy and Infectious Diseases awarded the TB Structural Genomics Consortium a five-year grant worth more than $28.5 million. Los Alamos will receive the grant, distribute the funds and coordinate the work among all the institutions.

Tuberculosis is the world's number-one infectious disease, claiming about two million lives annually.

"About one-third of all people in the world are infected with TB," said project leader Tom Terwilliger of Los Alamos' Bioscience Division. "In fact, many people who die of complications caused by AIDS actually die from TB.

"The number of new TB cases is on the rise, especially in Third World countries," Terwilliger added. Most infected people do not get the disease as long as their immune systems are strong, but Mycobacterium tuberculosis, which causes the disease, takes advantage of weakened immune systems and grows into full-blown disease in about 5 to 10 percent of infected people.

The new consortium's goal is to determine the structures and shapes of approximately 400 functional proteins from Mycobacterium tuberculosis.

All living organisms possess proteins, highly complex substances that incorporate many biological compounds directly involved in the chemical processes essential for life. By determining the structures and shapes of these proteins, researchers in structural genomics can determine how M. tuberculosis works and design drugs that bind to the proteins and inhibit their activity, killing the organism, and vaccines that protect against the disease.

Consortium members Lawrence Livermore National Laboratory; University of California, Los Angeles; University of California, Berkeley; Texas A&M University; and the Albert Einstein School of Medicine will receive direct funding from Los Alamos. The entire consortium recently held a three-day retreat in Santa Fe that included a strategy session for the TB work.

Most of the participants, including Los Alamos, will work on determining the proteins' shapes. This involves engineering and producing purified proteins from M. tuberculosis' genes, crystallizing them and finally taking X-ray "snapshots" to obtain their shapes.

For its part, Los Alamos will use a technique developed by Geoffrey Waldo that fuses a green fluorescent protein with a target protein, so that it fluoresces only if the target protein is properly folded and thus suitable for purification and crystallization. This method also can turn improperly folded proteins into properly folded ones. The technique earned Waldo a Los Alamos Distinguished Performance Award this year. Los Alamos researchers led by Min Park will purify the engineered proteins. Both Waldo and Park work in Los Alamos' Bioscience Division.

After the purified proteins are crystallized in a special solution, they will be "photographed" using X-rays that strike the protein, are diffracted and deposited on an imaging camera. A special software developed by Terwilliger called SOLVE automatically analyzes the image and displays a picture of the protein's shape on a computer.

All information obtained from the project will be placed online at http://www.doe-mbi.ucla.edu/TB for other researchers and companies to use for free, noted Terwilliger.

"Tuberculosis is such a major worldwide problem, and we feel placing all this information immediately in the public domain is simply the right thing to do," he said.

Terwilliger, Waldo and Park, along with Joel Berendzen of Los Alamos' Physics Division, are the primary Los Alamos researchers involved in the program.

Los Alamos is internationally recognized as a leader in structural genomics. In addition to developing methods for engineering proteins and for automatically solving protein structures, Los Alamos researchers have taken a lead role in defining the new field of structural genomics and in showing how it will be important for developing a structural foundation for the future of biology.

Additionally, Los Alamos has been part of a pilot project with Lawrence Livermore, UCLA, UC Berkeley and the University of Auckland in New Zealand to determine the structure of proteins for the organism Pyrobaculum aerophilum.

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