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The gate of an ion channel in the inner membrane of the E. coli bacteria

Maryland Scientists are Using
the Power of Computers to Unlock the Mysteries
of Life.

Story by
Megan Michael

Amitabh Varshney faces a giant, three-dimensional Escherichia coli molecule that appears on a screen on his laboratory wall. He watches the geometry of the molecule change atom-by-atom as its channel transitions from a closed state to an open state. Such changes, and the relationship between the molecule's form and function, are central to Varshney's research in the health sciences. Some day, the patterns he observes on the wall could contribute to the discovery of new therapeutic drugs and drug-delivery systems.

Varshney's research is centered on understanding and solving biological problems, but he rarely comes in contact with active biological systems. Varshney is a computer scientist--his research is conducted via machines. The biological data for this project comes from co-investigator and biologist Sergei Sukharev, who is conducting fundamental research into the principles and structures of the E. coli bacterium. This computer scientist-partners-with-biologist model has become increasing popular at universities and research institutions across the nation as the rising field of computational biology promises to profoundly transform the future of biology.

Computers and Biology Converge

"Computational biology is the convergence of high-powered computer systems and biology," explains Joseph JaJa, professor and director of the University of Maryland Institute for Advanced Computer Studies. This new field is providing tools and approaches for studying biological problems ranging from how cells and proteins function at the molecular level to the creation of cell, tissue and organ models.

The development of the computational biology field has been two-fold. For more than a decade, researchers worked to determine the sequence of the human genome. Between 30,000 and 40,000 genes, which make up the building blocks of deoxyribonucleic acid, or DNA, were sequenced during the Human Genome Project, raising even more questions about genetic data. To answer the questions, scientists and researchers moved beyond the genome and have begun to analyze DNA sequences, identify and characterize ribonucleic acid, or RNA, and determine protein structures and functions. "All of these efforts have resulted in a wealth of biological data that needs to be analyzed and understood," says JaJa. "And the only way to accomplish this is through computational techniques and computer scientists working in close collaboration with biologists."

Revolutionary Possibilities

Computer modeling has long been used in fields from architecture to meteorology to engineering, but its applications in advanced molecular research only recently emerged as a subdiscipline of its own, computational biology. As a mountain of biological data began to pile up over the last decade--thanks in part to advances in the study of genes and proteins--the demand for computer analysis in biological research swelled. More specifically, scientists wanted to tap computers with large storage and memory capacity to support complex analysis of biological data. The ability to share data and disseminate research findings through the Internet and new interaction and visualization technologies have also greatly contributed to the importance of computers in biology research initiatives.

The profound impact of computer-based analysis on the life sciences has inspired leading research institutes and national research universities to invest more time, energy and money in this emerging research area. At the University of Maryland, that investment has taken form as the interdisciplinary Center for Bioinformatics and Computational Biology, which is headed by JaJa.

"The center helps link the university's strengths in computer science, mathematics and the life sciences," says JaJa. It includes researchers from the departments of biology, cell biology and molecular genetics, chemistry and biochemistry, computer science, entomology and mathematics who have joined together to work on projects ranging from data mining, functional genomics and evolutionary genetics to protein folding and 3-D graphics and scientific visualization. One of the major research projects coming out of the center is the collaboration between Sukharev and Varshney.

Molecular Modeling

Sergie Sukharev

Sukharev has been conducting fundamental research into the principles and structures of E. coli, a common intestinal bacterium, since the early 1990s. His research, which is sponsored by the National Institutes of Health, or NIH, and NASA, focuses on determining the structure and function of the bacterium's ion channels (small membrane proteins that transport ions in and out of cells) and the role that they play in physiology and mechanosensation.

"Ion channels can convert mechanical stimuli into cellular signals," says Sukharev. To better understand how ion channels function, Sukharev is studying the opening and closing of the gate of a large ion channel in the inner membrane of the E. coli bacteria. "When the gate opens, the ions can cross the membrane and generate a chemical or electrical signal. These signals then act as communicators and stimulate the performance of various functions."

Sukharev's basic research into the E. coli channel is providing a framework for the inner workings and molecular mechanisms of ion channels. Experts believe that the molecular mechanisms of ion channels are extremely important because nearly every cell in the human body uses ion channels for perceiving external stimuli, maintaining steady states, or for short- or long-range signaling. It is also believed that defective ion channels play a role in a variety of human diseases, such as cardiovascular disease, hearing and balance disorders, and some systematic congenital disorders, says Sukharev.

Further research into ion channels may prove useful for treating human diseases. It may also help in the discovery and design of new therapeutic drugs and drug-delivery systems. Mechanosensitive channels, like the channel being studied by Sukharev, can potentially be used as drug-delivery valves that release preloaded substances from carrier particles into the human body. But before new systems are developed, Sukharev and other researchers need to get a better understanding of the conditions under which the channels operate.

While researchers have become increasingly aware of the role that ion channels play in cellular function and dysfunction, little is known about their molecular structure. That's where the collaborations between biologists like Sukharev and computer scientists like Varshney become important.

"Computational tools for my research project are vital," says Sukharev, who also collaborated with Robert Guy, a researcher from NIH, to develop computer models of the channel's structures. "At this stage in my research, the calculation and visualization of the protein surfaces and cross sections [performed by Dr. Varshney] helps me better understand the energetics of the molecule's structural transitions. It also provides a tool for verification and for determining whether my hypothesis is sound or wrong."

Biological Visualization, Atom-by-Atom

Amitabh Varshney

In the Graphics and Visual Informatics Laboratory, Varshney and a team of computer scientists work to translate Sukharev's hypothesis about the transition between the closed and open states of the ion channel into hundreds of mathematical equations, algorithms and data structures. High-powered computers are programmed and then simulations of the atomic transitions are run on a wall-sized display. The E. coli molecule that appears on the screen allows the researchers to see in virtual reality the geometry of the molecule change atom-by-atom as its channel transitions from a closed state to an open state.

"Dr. Sukharev provides my lab with different models of how the ion channel would potentially act," says Varshney. "Then we convert the models into 3-D graphics so that he can actually see whether the changes that he is expecting really make sense after he is able to visualize them. This is an example of graphics helping validate biological models."

One of Varshney's research goals, which will also benefit his collaboration with Sukharev, is to develop a computer model that allows interactivity to go hand in hand with the computations. "We'd like to achieve a high level of interaction so that biologists like Dr. Sukharev can compute the properties of the molecules and then interactively change the angle of the molecule or change the parameters of the computations. That way Dr. Sukharev would be able to get a better and more thorough understanding of how the changes are happening," says Varshney, whose research is sponsored by the National Science Foundation.

Making interaction a top priority has meant that Varshney and his research team have had to develop new, practical and easy-to-use tools. The real-time display screen that hangs in the lab is one result of this effort. "The system provides researchers a large field of view and a high resolution for visualization of the biological models," explains Varshney.

Using the display, researchers can easily work with each other--instead of cramming around a small computer screen--and interact with the biological models from different viewpoints. The team also has incorporated the use of ultrasonic trackers with the system so researchers can directly rotate, splice and otherwise manipulate the molecular structures right on the screen. "Using the tracker, researchers can actively explore the 3-D molecules and gain insight into their structure and function," says Varshney.

Varshney has been working on developing advanced visualization tools and techniques for medical applications for more than 10 years. "The computer revolution has really allowed for computers and 3-D graphics to become an increasingly important part of biology research," he says. "Computers are enhancing the ability of biologists to better identify what they are looking at--quite possibly to the equivalent of what the microscope did several centuries ago."

Systematic Drug Design

In addition to his collaboration with Sukharev, Varshney is partnering with other Maryland researchers on projects that range from protein and molecular modeling to rational drug discovery and development.

Traditional drug design--a hit-or-miss procedure--is a lengthy and costly process. Pharmaceutical companies and basic researchers alike are now turning their attention to a more rational and systematic method of drug design that involves computational biology. "Computer-aided drug design can significantly shorten the process," explains Varshney. This saves both time and money.

Rational drug design involves understanding how a 1-D sequence of amino acids folds itself into a 3-D protein structure, how that 3-D structure influences the function of the protein, and how a molecule (such as a potential drug) can dock on the active site of a protein. To help solve these issues, Varshney and his research team are developing models of the proteins and algorithms that help predict molecular docking.

The Biology of the Future

Although it's hard to predict exactly when the kind of collaborative research happening at Maryland will result in designer drugs and novel drug-delivery systems, experts are optimistic that the revolution is near.

"Right now, supercomputers and their capabilities are helping us develop the right tools that will allow biologists to make advanced scientific discoveries and solve complicated biological problems," says Varshney. "It is the technologies that will be developed in the next 10 to 15 years because of these tools that promise to substantially change the biology of the future."
-MM