The Biomedical Initiative


In 1987, the PSC biomedical program became the first extramural biomedical supercomputing program in the country funded by NIH. Since then, with support from NIH’s National Center for Research Resources (NCRR), PSC has fostered exchange between PSC expertise in computational science and experts in biology and medicine to solve important problems in the life sciences.

PSC workshops and courses on computational biology have trained more than 3,150 researchers in the use of high-performance computing for biomedical research, in such areas as sequence analysis in genome research, the structure of proteins and DNA, and biological fluid dynamics. “Our training reaches hundreds of biomedical scientists each year,” says David Deerfield, director of PSC’s biomedical initiative. “Techniques we’ve developed are helping scientists nationwide cope with the explosion of genome data.”

Since its inception, PSC’s biomedical program has provided computing resources for more than 1,000 biomedical research projects involving more than 2,500 researchers at 218 research institutions in 48 states. Among these are several projects featured in this Projects in Scienctific Computing, 2004 (Protein Motors Incorporated, Understanding Metalloenzymes & Signals for Cell Growth).

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Core Research

In addition to training and access to computational resources, PSC's biomedical group carries out its own core program of research in structural biology, protein and nucleic-acid sequence analysis, computational neuroscience and microphysiology and biomedical visualization.

Spatially Realistic Cellular Modeling

PSC scientist Joel Stiles, an associate professor in the Mellon College of Science at Carnegie Mellon University, leads PSC’s research in computational microphysiology. He is co-developer of MCell and DReAMM, software used in more than 100 laboratories around the world to simulate microcellular physiology.

Working with laboratory data from a patient with a neurological disorder called slow-channel congenital myasthenic syndrome, Stiles used MCell to successfully identify a previously unknown disease process. From MCell simulations, he deduced that receptors from a mutated protein in this particular patient were not only slow to close, but also slow to open, a previously unreported condition. Subsequent lab studies confirmed the finding — knowledge that can help in arriving at appropriate drug therapy as well as in research to develop better treatments.

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Computational Tools for Genomics and Proteomics

An expert in sequence analysis of DNA, RNA and proteins, PSC scientist Hugh Nicholas has used these techniques, in collaboration with University of Pittsburgh biologist John Hempel, to classify relationships among an important family of enzymes called aldehyde dehydrogenase (ALDH), which protect against toxicity and affect cancer treatment. The process involved, first, the alignment of 145 different ALDH sequences — one of the largest multiple-sequence alignments achieved.

Nicholas and Hempel then applied techniques they developed to identify recurring sequence-motifs. Their work charted the family relationships among 13 distinct ALDH sub-families they identified and developed new insight into the relationship between ALDH sequence and structure.

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Hybrid Quantum and Classical Enzyme Simulations

PSC scientist Troy Wymore collaborated with Deerfield, Hempel and Nicholas to elucidate the enzyme mechanism of a representative ALDH enzyme. He developed a methodology for combining high precision, but computationally expensive, quantum simulations with classical molecular dynamics. His simulations uncovered a novel chemical event — a proton transfer from the ALDH enzyme backbone.

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Force-Field Models for Molecular Dynamics

Charles Brooks of the Scripps Research Institute also does core research through the PSC biomedical initiative. His work involves the challenge of protein modeling, for which an important key is accurate “force fields” — the mathematical expression of energy relations among the atoms of the biomolecule being simulated.

Brooks is a pioneer in this area, having helped to develop the widely used force-field model, CHARMM. His recent work has been to develop atomic-level force-field models to faithfully represent the distribution of electric charge within biomolecules, critical for understanding the function of membrane proteins.

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Viewing 3D Data: The PSC Volume Browser

PSC’s biomedical initiative developed PVB, a graphical interface and rapid-retrieval system that enables users to rapidly view large 3D images over the internet. Viewing is interactive, with freedom to choose any angle or cross-sectional slice through the data to see from the inside. Because it allows viewing of uncompressed datasets from desktop computers, PVB is a breakthrough in 3D imaging.

PVB’s network-delivery system allows up to 40 people to navigate independently through the data in near real-time. To gain speed, PVB also employs innovative data-compression that, for the most compressible data, achieves a ratio greater than 30:1. Used with the National Library of Medicine’s Visible Human, PVB provides a versatile anatomy resource. In recent work, PSC has applied PVB to a similar large-volumetric dataset called the Visible Mouse.

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