New systems biology center positions UT Southwestern in vanguard of scientific research

02/20/04

DALLAS Feb. 20, 2004 Scientists have spent the past 50 years taking apart biological systems piece by piece. Now the future of biological research depends on putting them back together, says Nobel Laureate Dr. Alfred Gilman.

"One of the most daunting challenges in biology and medicine is to begin to understand how all the 'parts' of cells genes, proteins, and many other molecules work together to create complex living organisms," said Dr. Gilman, chairman of pharmacology at UT Southwestern Medical Center at Dallas.

Dr. Gilman is heading up a new research center devoted to systems biology research. Scientists in the Cecil H. and Ida Green Comprehensive Center for Molecular, Computational and Systems Biology at UT Southwestern will link basic research on molecules and cells with analysis of how entire biological systems function, both in health and in sickness. The center was made possible by a $12.8 million gift from the Cecil and Ida Green Foundation.

"The time is really right for this kind of focused research effort," said Dr. Gilman.

The emerging field of systems biology focuses on how individual parts of an organism from small-scale molecules and proteins to larger-scale cells and tissues work in concert to produce a functioning or in the case of disease, malfunctioning life form. Even though the research goals are not new, recent advances in technology make tough problems in biology ripe for such a comprehensive and coordinated scientific attack.

In systems biology, experts in scientific disciplines including biology, physics, mathematics and computer science come together to create models of biological systems that consider not only the individual parts but also how they react to each other and to changes in their environment.

Integrating the power of computational science and advanced imaging technologies with basic molecular and cellular research will allow remarkable insights to be gained about how living systems function, Dr. Gilman said.

"Imaging is an important part of understanding various systems," he said. "We have superb imaging facilities at UT Southwestern, which include very talented scientists in the areas of X-ray crystallography and nuclear magnetic resonance spectrometry. This particular area of strength in molecular imaging is invaluable to our systems biology endeavors."

To aid such efforts, UT Southwestern researchers recently acquired one of the most powerful scientific instruments used to study the molecules of life. About 15 feet tall, 10 feet across and weighing nearly four tons, an 800-megahertz nuclear magnetic resonance (NMR) spectrometer was delivered to the campus in November. Funded by a $2 million grant from the National Institutes of Health, the NMR device allows scientists to produce three-dimensional images of proteins and other biological molecules in solution, which is similar to proteins' natural environment within cells.

"Where the real power comes in studying complex systems is being able to see how things like proteins move and change over time," said Dr. Rama Ranganathan, director of the Systems Biology Division of the Green Comprehensive Center and associate professor of pharmacology at UT Southwestern. "Large magnets such as this allow us to really look a lot more closely at protein dynamics."

Dr. Gilman said one goal of systems biology is to develop a computer model of an entire cell. Such a model would revolutionize drug development, allowing the most promising drugs to be identified more quickly and in a more rational, informed way.

"It can cost a billion dollars to develop one drug these days," Dr. Gilman said. "Drug companies can only afford to develop drugs they think will have a large market, medications that will return a company's huge investment. Using computer models to develop and test new drugs 'in silico,' in combination with experiments in the lab, will be faster than the current process and substantially reduce the enormous cost of drug development."

At the heart of systems biology is, of course, biology. UT Southwestern has in place a large cadre of people, equipment and expertise devoted to investigating and understanding various biological processes. A core group of faculty already is applying computer science and mathematics in their work. Dr. Gilman said that in addition to a small initial group of existing UT Southwestern faculty, he and Dr. Ranganathan plan to recruit a number of new scientists to the center with expertise in areas that support the center's efforts, including researchers knowledgeable in physics, computer science and math that will radically enlarge present efforts.

The new center also will provide an opportunity for UT Southwestern scientists to collaborate with other UT System institutions, which have considerable computing resources and faculty expertise.

"Communications systems have gotten to the point where you don't have to have all your components and resources on the same campus," Dr. Gilman said. "In our case, it will be more efficient and cost-effective to connect with a general academic campus for any additional computer resources we may need."

One of the key areas of study in systems biology is how proteins function within cells and how that function translates to health. Proteins are large molecules that make up about half of the material within the body's cells. They are involved in all essential life functions, from immune response and muscle contraction to cholesterol and hormone regulation.

Dr. Ranganathan and his research group specialize in determining the structure and function of proteins, as well as ways that cells signal each other to carry out certain tasks. Their studies of light-gathering cells, or photoreceptors, in the eye provide a good example of the type of problem systems biology can address.

Photoreceptors in the retina convert light into electrical signals, which then pass into the brain where they are interpreted, resulting in vision. Proteins within these cells are responsible for that conversion of light into electrical signals. Researchers have identified 50 to 100 proteins in these cells, all working together to carry out this function.

"Scientists have spent the past 30 years delineating all the parts of this photoreceptor cell. We know all the proteins, all their names, even what they do individually. But we still don't understand how the group of them act together to produce this electrical response to light," Dr. Ranganathan said. "To get that, and ultimately to better understand how vision works, we have to develop some way to study the aggregate behavior of these 50 to 100 proteins."

Dr. Ranganathan and his colleagues use a variety of sophisticated equipment and techniques to study proteins and other molecules. For example, his group is among the few to integrate data from X-ray crystallography, genetic analysis and advanced imaging techniques into one report on a single protein, ushering in a new way to present a story about how a protein works in an organism.

Beginning with X-ray crystallography data, Dr. Ranganathan's group used advanced computer science and mathematics to determine the three-dimensional atomic structure of one protein involved in converting light into electrical signals. They also used genetic analysis to create a mutant fruit fly carrying an altered form of that protein in its photoreceptor cells. By studying these mutant flies, they hope to understand the meaning of the protein's structure for visual signaling.

"This effort is really a microcosm of what systems biology is all about," Dr. Ranganathan said. "It seems such a special thing today, but it's not unreasonable to think that this interface between physics, engineering, math and biology will be the norm at every research institution 25 years from now."

Source: Eurekalert & others

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