Syndicate content

Archive - Mar 20, 2011

Mutant Prions Can Help Correct Misfolding of Proteins

Clumps of misfolded proteins are prime suspects in many neurological disorders including Alzheimer's, Parkinson's, and Creutzfeld-Jakob disease. Those diseases are devastating and incurable, but a team of biologists at Brown University reports that cells can fix the problems themselves with only a little bit of help. The insight suggests that there are more opportunities to develop a therapy for protein misfolding than scientists had thought. "There are multiple steps that you could target," said Susanne DiSalvo, a Brown biology graduate student and lead author of a paper published online on March 20, 2011, in Nature Structural & Molecular Biology. In the study, the research team, led by Dr. Tricia Serio, associate professor of medical science, explains how two different beneficial mutant prions managed to foil the amplification of harmful clumps of misfolded proteins in yeast. Cells have an internal quality assurance system to break up and refold misfolded proteins, but that system can be overwhelmed by diseases. DiSalvo was the first to observe that the mutants act at distinct stages to tip the balance back in favor of the cells, allowing them to overcome the problem. Dr. Serio says the molecular mechanisms appear to explain how similar mutants solve protein misfolding in mammals, including people. The phenomenon had been poorly understood and has never been exploited to develop a successful therapy. Until now most scientists guessed that the only way to stop the runaway misfolding was right at the beginning and assumed the mutants must be blocking that first step to keep the protein in a harmless form. DiSalvo's work instead suggests that there are many opportunities throughout the process where even a mild intervention could give cells what they need to gain the upper hand, Dr. Serio said.

LNA-Based Compounds Can Inhibit Entire Disease-Associated MicroRNA Families

A study published online on March 20, 2011, in Nature Genetics demonstrates that tiny locked nucleic acid (LNA)-based compounds developed by Santaris Pharma A/S can inhibit entire disease-associated microRNA families. This provides a potential new approach for treating a variety of diseases including cancer, viral infections, cardiovascular and muscle diseases. Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the research and development of mRNA and microRNA targeted therapies, developed the tiny LNA-based compounds, which are 8-mer LNA oligonucleotides, using its proprietary LNA Drug Platform. The high affinity and target specificity of tiny LNA-based compounds enabled functional inhibition of both single microRNAs and entire microRNA families in a range of tissues in vivo without off-target effects. MicroRNAs have emerged as an important class of small regulatory RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression associated with many diseases. Because they dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets in the treatment of many disease processes. "Using tiny LNA-based compounds to successfully inhibit entire disease-associated microRNA families provides a new range of opportunities to develop novel microRNA-targeted drugs for both in-house drug discovery programs, as well as with our partners," said Dr. Henrik Ørum, Vice President and Chief Scientific Officer of Santaris Pharma A/S.

Berkeley Scientists Discuss Systems Biology Advances in Review Issue of Cell

Dr. Adam Arkin, director of the Physical Biosciences Division of the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory and a leading computational biologist, is the corresponding author of an essay in the March 18, 2011 issue of Cell which describes in detail key technologies and insights that are advancing systems biology research. The paper is titled “Network News: Innovations in 21st Century Systems Biology.” Co-authoring the article is Dr. David Schaffer, a chemical engineer with Berkeley Lab’s Physical Biosciences Division. Both Drs. Arkin and Schaffer also hold appointments with the University of California (UC) Berkeley. The Cell issue is devoted to reviews of systems biology. “System biology aims to understand how individual elements of the cell generate behaviors that allow survival in changeable environments, and collective cellular organization into structured communities,” Dr. Arkin says. “Ultimately, these cellular networks assemble into larger population networks to form large-scale ecologies and thinking machines, such as humans.” In their essay, Drs. Arkin and Schaffer argue that the ideas behind systems biology originated more than a century ago and that the field should be viewed as “a mature synthesis of thought about the implications of biological structure and its dynamic organization.” Research into the evolution, architecture, and function of cells and cellular networks in combination with ever expanding computational power has led to predictive genome-scale regulatory and metabolic models of organisms. Today systems biology is ready to “bridge the gap between correlative analysis and mechanistic insights” that can transform biology from a descriptive science to an engineering science.

New Strategy for Extending Useful Life of Antibiotics

A team of scientists from the University of Oxford, U.K., has devised a new strategy that could one day slow, possibly even prevent, the spread of drug-resistant bacteria. In a new research report published in the March 2011 issue of GENETICS, the scientists show that bacterial gene mutations that lead to drug resistance come at a biological cost not borne by nonresistant strains. They speculate that by altering the bacterial environment in such a way to make these costs too great to bear, drug-resistant strains would eventually be unable to compete with their nonresistant neighbors and die off. "Bacteria have evolved resistance to every major class of antibiotics, and new antibiotics are being developed very slowly; prolonging the effectiveness of existing drugs is therefore crucial for our ability to treat infections," said Dr. Alex Hall, a researcher involved in the work from the Department of Zoology at the University of Oxford. "Our study shows that concepts and tools from evolutionary biology and genetics can give us a boost in this area by identifying novel ways to control the spread of resistance." The research team measured the growth rates of resistant and susceptible Pseudomonas aeruginosa bacteria in a wide range of laboratory conditions. They found that antibiotic resistance has a cost to bacteria, and this cost can be eliminated by adding chemical inhibitors of the enzyme responsible for resistance to the drug. Leveling the playing field increased the ability of resistant bacteria to compete effectively against sensitive strains in the absence of antibiotics. Given that the cost of drug resistance plays an important role in preventing the spread of resistant bacteria, manipulating the cost of resistance may make it possible to prevent resistant bacteria from persisting after the conclusion of antibiotic treatment.