The future, for James C. Sacchettini, Professor of Biochemistry and Biophysics, is held in a three-dimensional puzzle of crystallized proteins. With every protein structure he examines, the holder of the R.J. Wolfe-Welch Chair in Science hopes to find another piece of a complex genetic and biochemical puzzle, leading ultimately to new drugs that will prevent the spread of infectious diseases.

Professor Sacchettini and his collaborators, including a team of Texas A&M graduate and post-doctoral students, focus primarily on Mycobacterium tuberculosis, the bacteria that causes tuberculosis (TB). The bacteria can remain dormant in the lungs for years, activating when a person’s immune system is compromised. The spread of AIDS in developing countries has triggered a dramatic rise in TB, with strains that are resistant to existing drugs. An estimated two billion people now carry the bacteria, and experts predict that 30 million people could die of TB in the next 10 years.

Thus, the race to design new drugs to combat TB is one of academic medicine's most pressing issues. Sacchettini’s team is among a select group of biochemists nationwide participating in the first structural genomics study of Mycobacterium tuberculosis. Structural genomics is the next generation of genome research, enabling scientists to build complete, three-dimensional portraits of the entire repertoire of DNA and proteins that direct chemical reactions in bacteria.

During the five-year study, the collaborating labs will dissect as many as 1,000 of the 4,000 proteins genetically coded in TB, enabling insights into how these bacteria survive in humans by evading their immune systems. “This is the future of structural biology,” Sacchettini says. “The structures we determine will tell us so much about how a protein functions, how it interacts with other proteins—providing all kinds of information that's not available currently from the one-dimensional genome model. We’re going to understand much more about biology and disease—not just of the TB bacteria, but of many different organisms since many infectious pathogens use similar strategies to survive in the human host.”

Sacchettini’s lab also investigates malaria, staphylococcus and streptococcus bacteria, Lyme disease and amyloid diseases, including Alzheimer’s and TTR amyloidosis. “Many of the diseases we’re working on are either ‘orphan’ diseases, meaning they are rare in the human population, or diseases that occur primarily in developing countries,” he adds.

Sacchettini hopes that, after his project brings comprehensive TB information to the public genome database, TB drug design will be economically viable for pharmaceutical and biotechnology companies.

“Having the TB genome structurally characterized will reduce the R&D burden for companies interested in TB. It also will contribute to our ability to develop new and effective vaccines,” he says.

Sacchettini’s work is done under the aegis of the Center for Structural Biology at Texas A&M. He also operates a lab at Texas A&M’s Institute of Biosciences and Technology in Houston. Through the new structural biology class he co-teaches with Dr. Andy Liwang, Sacchettini is also passing cutting-edge technology along to the next generation of biochemists. “The techniques students are learning will have wide applications in the future,” he says. “As it becomes more routine, structural biology will also influence the creation of better agricultural herbicides and bio-engineered foods.”

Although much of Sacchettini’s collaborative research is funded by the National Institutes of Health, none of it would be possible without funds from his endowed chair. “The Welch Foundation has been a huge contributor, not only to my work, but the whole area of chemistry and life sciences at Texas A&M. Their very generous endowment of my laboratory and their funding of colleagues elevates the level of research here tremendously,” he says.