Mike Sinclair and Jeri Timlin
Understanding Genes
October / November 2004
Volume 2 Number 5
Researchers at Sandia National Laboratories have parlayed a Laboratory Directed Research and Development (LDRD) project into a wide-ranging, life sciences R&D program that has received funding from the federal and state governments and a private foundation.
One of the more powerful technologies in biology today is the DNA microarray, a tool for understanding differential gene expression, which is the translation of the information contained in a cell's DNA into the proteins that perform critical cellular functions. The microarrays themselves are small glass slides that contain thousands of regularly arranged samples of genes. To collect information on gene expression, researchers attach fluorescent dye tags to the DNA and then scan the tags on the microarrays to determine the genes being expressed. Current commercial microarray scanners use univariate methods, which look at only one variable at a time, to quantify a small number of fluorescent dyes on printed microarray slides. Sandia has developed a hyperspectral DNA microarray scanner that, in conjunction with their multivariate curve resolution (MCR) algorithms, can extract more useful information from DNA microarrays.
Sandia's project has improved microarray technology in several important areas, including the reliability and precision of laboratory measurements, and has enabled substantially faster analysis and discovery of the biological meaning from the experiments.
Advances in Genomics
Recent advances in genomics, supported by these technologies, are bringing about a revolution in understanding of the molecular mechanisms of disease, including the complex interplay of genetic and environmental factors.
High-throughput instruments and analysis techniques, such as microarrays, hyperspectral scanners, and MCR algorithms are required to make good use of the genomic sequences that have recently become available for many species, including humans. These instruments and methods must work with tens of thousands of genes at once and be able to identify the small subset of those genes that are implicated in, for instance, diseases and treatments.
Sandia and the University of New Mexico are working together to gain a greater understanding of genomics and ultimately to find new ways to diagnose, treat, and prevent illnesses. Sandia researchers George Davidson and David Haaland have been collaborating with UNM researchers on two different projects using several of the same microarray scanning and computing technologies.
In one project, Haaland and Davidson are collaborating with Maggie Werner-Washburne, a UNM biology professor, to improve microarray analysis techniques and the interpretation of data from microarray experiments. Focusing on yeast cells, the fundamental research promises to provide better understanding of how cells transition from a resting to a growing state, which is involved in wound responses, cancer, the germination of spores, and the complex response of cells to bioagents. "The collaborations between Sandia and UNM have been quite successful," Davidson says. "Importantly, we jointly developed the ability to conduct and analyze microarray experiments using either commercial gene array membranes or arrays printed on glass slides by the UNM biology department."
Werner-Washburne describes the outcome, "As a result of our Sandia collaborations, we have been able to take a systems approach to this problem. There are very few laboratories in the country that effectively incorporate biologists, computer scientists, chemists, mathematicians and engineers at this level. It is the future of genomics, and we have a unique opportunity to make important contributions and have fun at the same time."
Genomes to Life
One goal of the project is to help stabilize atmospheric carbon dioxide to counter global warming. The understanding, predicting and perhaps manipulating carbon-fixation in the oceans is of interest to a broad audience of scientists and policymakers.
Sandia, though not particularly known for biological expertise, was awarded its leadership role for its other expertise, explains Grant Heffelfinger, Sandia's Genomes to Life program manager. The program has four goals: to understand the molecular machines of life, regulatory networks, and how microbial communities work together. The fourth goal is to develop computational capabilities to address the first three. So our proposal, though it has a biological title, is based on our world-class computing and experiment-analysis expertise —€” abilities we've proven time and time again."
A strategy that could be used to counter greenhouse-gas buildup (an influence on global climate) is to alter natural biological cycles to store extra carbon in the earth and the ocean. This approach will be tied to the metabolism and activities of communities of microbes. It is hoped that research into their enzymes, regulation, and environments will lead to new ways to store and monitor carbon, but at the present time, the biochemical mechanisms of carbon-fixation in these microbes is poorly understood. In this project, Sandia leads an investigation, using experimental and computational methods, of the carbon-sequestration behavior of Synechococcus Sp., an important, abundant marine microbe, for environmental responses to carbon dioxide levels.
Whether for fundamental cell research, cancer treatments, or carbon-fixation in the world's oceans, Sandia's hyperspectral microarrays and supporting computational expertise are exciting new tools in the field of systems biology.
According to David Haaland, while the current applications of the hyperspectral scanner are important, the potential future applications of this technology are stunning. Imagine being able to determine how, precisely, memory is stored in the brain. Or, using the enhanced spatial resolution of a 3-D version of the scanner to monitor the microfluidic synthesis of quantum dots or observe motor proteins scrambling over structures or discover how cells signal one another.
Haaland is convinced that there will be many more applications for the system and additional intellectual property, primarily in the algorithms.
Margaret Lovell is a senior technical writer at Technically Write, assigned to Sandia National Laboratories.
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