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Pathways underlying disorders



ORNL mice and rabbits (studied elsewhere and shown above) are potential models for children suffering from a condition wherein skull bones grow very fast and fuse prematurely, causing facial abnormalities and preventing further brain growth.
Click here for a high resolution photograph.

Abnormalities of the face and skull rank among the most common birth defects in humans. Understanding such complex human disorders requires a systems biology approach, according to Cymbeline Culiat, a molecular geneticist in ORNL's Life Sciences Division. She is taking this approach as she investigates a series of eight mutant mouse strains that could serve as animal models for deciphering the complex molecular interactions underlying skull development.

"We found that these eight mutations occurred in the same gene and that this gene codes for a novel cell-signaling protein critical to the development of bones in both the skull and spine," Culiat says. "This collection of mutant mice carrying different changes in the same protein gives us an excellent opportunity to understand that particular protein's various functions."

In the mutations being studied by her group, when one part of the protein is affected by a mutation, a mouse may be born with a deformed skull and face but a normal spine. If another portion of the protein is affected, severe defects in both the skull and spine occur. In this gene's most severe mutation (designated 102DSJ), the amount of protein being made is greatly reduced. The mice with this mutation exhibit extreme alterations in spine curvature and skull anomalies.

"Our mice are potential models for children suffering from craniosynostosis (CS), a condition wherein skull bones grow very fast and fuse prematurely, preventing further brain growth," she says. "Children with CS undergo major skull reconstruction at an early age and can suffer from mental retardation, visual and hearing impairment, and skeletal defects of the limbs and spine.

"Some children with CS manifest the same type of spinal defect observed in our mutant mice and some do not," Culiat continues. "If we can figure out why and how the mutant protein in our mouse models affects both the developing skull and spine, we will better understand this complex human disorder."

The availability of mouse and human genome sequences, rapid advances in technologies for detecting and measuring changes in gene expression, and computational tools for analyzing vast amounts of data are allowing Culiat and her associates to seek answers to systems biology types of questions: Which groups of genes interact and how do proteins interact to ultimately control the development of specific biological structures or perform certain functions? When a mutation occurs in a key gene in a pathway, how does the resulting perturbation in the pathway's other genes ultimately lead to a disease or abnormality?

Culiat established a collaboration with Mark Shannon of Applied Biosystems-Celera, which has developed sophisticated gene expression technology. Shannon wanted to test his company's technology on a large scale, to determine how useful it is for studying biological pathways in a whole organism--such as a mutant mouse.

Using bioinformatics data, the collaborators initially studied 300 genes in normal mice, as well as in mutant mice carrying the most severe mutation (102DSJ). The genes are involved in bone, cartilage, and brain development and in cell proliferation and differentiation. The researchers also assayed the expression of genes coding for proteins that could potentially interact with the mutant protein, based on knowledge of the predicted functional domains.

Shannon's lab performed thousands of very sensitive assays of RNA samples extracted from mouse embryos. The results showed that 33 out of 300 genes were significantly perturbed and that the majority of the genes exhibited reduced expression in all mice with the 102DSJ mutation.

"Most of the affected genes are involved in biological processes that are critical for the maturation of precursor bone cells," Culiat says. "Some of the genes were perturbed only in the head but not in the body, while others showed alteration in expression in the body but not in the head."

Culiat hopes future research on protein interactions will shed light on the inherent complexity of biological processes underlying such genetic disorders.

Microbes on a Mission The Department of Energy seeks to understand the diverse range of biochemical pathways that enable single celled organisms to survive under extreme conditions--high temperature, high radiation, and high concentrations of toxic chemicals. DOE is interested in harnessing the genes of these microbes, whose capabilities could help DOE meet its missions in environmental bioremediation, carbon sequestration to slow climate change, and energy production. ORNL researchers and their collaborators are studying these microbes as part of DOE's Microbial Genome Program and Genomics: GTL Program.



Computer visualization of an E. coli bacterial protein using Visual Molecular Dynamics software.
Click here for a high resolution photograph.

Multitalented bacteria of interest to DOE include Deinococcus radiodurans, which can withstand high doses of radiation because these cells efficiently repair radiation damage. Like Shewanella oneidensi, which is also studied at ORNL, these bacteria reduce certain metals--that is, they donate electrons to toxic metals, like chromium and uranium, so they can extract energy from carbon. When these metals accept the electrons, they often are converted from a soluble to an insoluble state, possibly enabling bioremediation.

Questions that drive some ORNL research include the following: How will these bacteria respond to the stress of a soil or groundwater environment loaded with toxic and radioactive metals? Will some bacterial cells convert radioactive uranium in storage ponds from a soluble to an insoluble form so that this toxic metal sinks into the sediments or stays put in soil instead of dissolving in water that may flow off-site? Can a microbe like Deinococcus radiodurans be "designed" so that more of its genes focus on remediating sites with mixed wastes--combinations of radioactive materials and toxic metals? Can a uranium-contaminated site be populated with Shewanella oneidensi or some other bacteria "trained" to remove uranium from groundwater and moist soil, saving DOE billions of dollars in toxic waste cleanup activities?

Certain bacteria in the ocean and on land take up carbon dioxide from the atmosphere and perform photosynthesis. Can genes from these bacteria be harnessed to help DOE halt the buildup of atmospheric carbon dioxide from energy production? Can the poplar tree be designed to grow faster and take up more atmospheric carbon dioxide that will be stored in its branches and roots? Can systems biology find ways to ensure that more carbon from decaying roots stays locked up in soil rather than being released back into the atmosphere?

DOE is also interested in microbes that produce clean fuels, such as methane, methanol, and hydrogen. ORNL researchers and their collaborators are focusing on Rhodopseudomonas palustris as a potential energy source. Can it be grown in a certain way or can its genes be harnessed to produce hydrogen efficiently? Can enough hydrogen be produced biologically for use in power-producing fuel cells for cars and buildings in the envisioned hydrogen economy?

Researchers in ORNL's Environmental Sciences Division are addressing these and other key scientific questions about the microbial community: What is the genetic diversity of microbial communities? How do environmental disturbances, such as contaminants, affect the structure, functional stability, and adaptive capacities of microbial communities? Can the diversity and metabolic capabilities of a microbial community be manipulated to achieve desired functions, such as remediation of mixed-waste contaminants?

To understand how a cell works, researchers must understand how protein complexes do the work of the cell. Questions that ORNL biologists are asking and hope to address using systems biology include the following: Why does a certain protein complex behave the way it does? How far can a protein complex be twisted so that it does something a little different better, cheaper, and faster than it did before? Will the protein complex meet our needs yet still survive? If a certain genetic part of a mutant E. coli bacterium is knocked out, will the bacterium suddenly produce more succinic acid for making useful products? If bacteria capable of anaerobic digestion are grown on a particular feedstock, will large amounts of methane be produced all the time, even when the feedstock is changed? To save time and money, could a biology experiment be simulated on a computer and confirmed in the laboratory?

These and other questions are driving biological research at ORNL and fueling the revolution in post-genome biology.

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