Systems Biology Provides First Global Analysis Of Prion Disease In A Mouse Model

Main Category: Biology / Biochemistry
Article Date: 31 Mar 2009 - 3:00 PDT

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Researchers at the Institute for Systems Biology (ISB) in Seattle and the McLaughlin Research Institute in Great Falls, Montana, published in Molecular Systems Biology a ground-breaking study which modeled the progression of degenerative brain diseases, one of which is "mad cow disease," that are caused by misfolded proteins called "prions". The paper can be accessed at http://www.nature.com/msb/index.html.

The study is perhaps the first comprehensive use of a "systems approach" leading to fundamental new insights into degenerative brain disease, as well as paving the way for new approaches for early diagnosis. The systems approach employs comprehensive (global) studies of informational molecules in the brain throughout the course of the disease and permits the construction of predictive models regarding disease mechanisms.

A review of the study in the same edition of Molecular Systems Biology by Gilbert S. Omenn, M.D., Ph.D., professor of Internal Medicine, Human Genetics, and Public Health Director at the University of Michigan Center for Computational Medicine and Biology, lauded the study as likely to become a landmark paper in systems biology for its methods and findings.

"This study is an example of how predictive network models of disease can be used to understand disease in an entirely new way, not as collections of symptoms, but rather as systems of interacting biological molecules that are not working properly," said Leroy Hood, M.D., Ph.D., president and co-founder of ISB. "Understanding these biological systems will allow us to diagnose, treat and ultimately prevent neural degenerative diseases. This systems approach will be a powerful new tool for studying virtually any type of disease."

ISB and McLaughlin researchers analyzed the complete populations of brain messenger RNAs in infected and control animals at 10 different time points during the disease progression. From these data, the research team was able to identify about 300 changing messenger RNAs that encoded the core prion disease response.

The identification of these RNAs enabled researchers to discover and describe four biological networks that explain virtually every known aspect of prion disease. The research team was also able to determine that about 100 of these prion-core RNAs encoded aspects of this disease that were previously unknown. Three of the four biological networks are also apparently involved in human neurodegenerative diseases such as Alzheimer's and Huntington's diseases. These studies also suggested possible new approaches to therapy for prion disease and other neurodegenerative disease.

Based upon the analysis of the disease-perturbed networks, researchers were also able to identify several protein blood biomarkers that indicate the presence of prion disease prior to the development of symptoms. Early detection can be important both for the management and more effective treatment of many diseases.

George Carlson, Ph.D., Director of the McLaughlin Research Institute in Great Falls, Montana, pointed out the importance of modeling disease in mice. "Mice offer the tremendous advantage of being able to track disease-associated changes in the target organ, in this case the brain, well before clinical illness appears," he said.

"We then look for changes in the blood that track with changes in the brain in mice that could be used as diagnostic signatures in specific disease models, such as frontotemporal dementia or Alzheimer's disease," said Carlson. "Results from mice will point the way for identification of blood diagnostic tests in humans."

These studies were based on approximately 30 million measurements, which required researchers to develop a series of powerful new software programs for analyzing, integrating and finally modeling these enormous amounts of data.

About the McLaughlin Research Institute

The McLaughlin Research Institute is an independent non-profit research organization in Great Falls, Montana near the Rocky Mountain Front. Research at the institute focuses on understanding the genetic control of normal development and disease susceptibility using the mouse as a model system. The Institute began in 1954 as the Laboratory for Experimental Medicine founded by Dr. Ernst Eichwald, a pioneer in transplantation genetics. Current research by its four research teams and forty-plus staff members emphasizes application of mouse genetics to understanding neurological disorders including Alzheimer's disease, prion disorders, Parkinson's disease, epilepsy, peripheral neuropathy, and sensory disorders. For more information on MRI visit: http://www.montana.edu/wwwmri

About the Institute for Systems Biology

The Institute for Systems Biology (ISB) is an internationally renowned, non-profit research institute headquartered in Seattle and dedicated to the study and application of systems biology. Founded by Leroy Hood, Alan Aderem and Ruedi Aebersold, ISB seeks to unravel the mysteries of human biology and identify strategies for predicting and preventing diseases such as cancer, diabetes and AIDS. ISB´s systems approach integrates biology, computation and technological development, enabling scientists to analyze all elements in a biological system rather than one gene or protein at a time. Founded in 2000, the Institute has grown to 14 faculty and more than 250 staff members; an annual budget of more than $35 million; and an extensive network of academic and industrial partners. For more information about ISB, visit http://www.systemsbiology.org.

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Institute for Systems Biology

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