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Archive - 2011 - Story

October 30th

Fragile X Protein Plays Key Role in RNA Editing

The most common form of heritable cognitive impairment is Fragile X syndrome, caused by mutation or malfunction of the FMR1 gene. Loss of FMR1 function is also the most common genetic cause of autism. Understanding how this gene works is vital to finding new treatments to help Fragile X patients and others. Researchers from the Perelman School of Medicine at the University of Pennsylvania, and colleagues from Brown University, have identified the FMRP protein (encoded by FMR1) as a key player in RNA editing, a process in which the working copies made from DNA, called messenger RNAs, are chemically altered after being transcribed from the genome. The scientists’ findings were published online on October 30, 2011 in Nature Neuroscience. Because RNAs are used as the instructions to make proteins, mistakes in RNA editing at the neuromuscular junction (NMJ), the site at which motor neurons innervate muscle, may cause problems in nerve function. Previous work at Penn and several other institutions strongly suggested the role of FMRP to be in regulating the translation of certain types of RNA at the synapse, the space between two nerves, or between nerves and muscles. "Most of the field has been focused on looking at FMRP interacting with specific RNAs and how it regulates their translation at the synapse," states lead author Dr. Thomas A. Jongens, associate professor of genetics at Penn. "Here we've tapped into identifying a function that FMRP has in regulating another process called RNA editing that is important in regulating neural activity." In RNA editing, the information encoded by DNA into an RNA molecule is altered, thus affecting the functioning of the proteins encoded by that RNA.

Scientists ID Misfolded Protein Form That Best Predicts Neuron Death in Huntington’s Disease

Scientists at the Gladstone Institutes in San Francisco, California, have discovered how a form of the protein linked to Huntington's disease influences the timing and severity of its symptoms, offering new avenues for treating not only this disease, but also a variety of similar conditions. In a paper published online on October 30, 2011 in Nature Chemical Biology, the laboratory of Gladstone Senior Investigator Dr. Steven Finkbeiner singles out one form of a misfolded protein in neurons that best predicts whether the neuron will die. Neuronal death is key to the development of Huntington's symptoms—including erratic behavior, memory loss, and involuntary muscle movement. This research underscores the value of the cross-disciplinary work done at Gladstone—a leading and independent biomedical–research organization—while revealing techniques that scientists anywhere can apply to conditions involving misfolded proteins, such as Alzheimer's disease and type 1 diabetes. "Effective treatments for diseases such as Huntington's and Alzheimer's have been slow to develop," said Dr. Finkbeiner, whose research at Gladstone investigates the interactions between genes, neurons, and memory. "We hope that our newfound understanding of precisely which misfolded proteins contribute to disease symptoms will speed up drug development for sufferers." Huntington's, an ultimately fatal disease that affects more than a quarter of a million people nationwide, is caused by mutations in the gene that creates the huntingtin, or htt, protein. As the mutated gene produces htt, a segment of the protein called polyglutamine is mistakenly expanded, distorting htt's natural shape and function. As a result, the misfolded protein malfunctions and can be toxic.

New Malaria Vaccine Addresses Different Forms of the Disease

A new malaria vaccine could be the first to tackle different forms of the disease and help those most vulnerable to infection, a study suggests. The new vaccine is designed to trigger production of a range of antibodies to fight the many different types of parasite causing the disease. Scientists created the vaccine by combining multiple versions of a key protein found in many types of malaria parasite, which is known to trigger production of antibodies upon infection. Mixing multiple proteins from various parasite types induces antibodies against a wide range of the parasites causing the disease. Researchers from the University of Edinburgh, who developed the vaccine, say that because malaria parasites exist in many forms, the only way to gain natural immunity against all strains is by having multiple bouts of the illness. A vaccine that overcomes this could be especially useful in children and other vulnerable groups of people. Many previous vaccines against malaria have had limited success because they target only a limited part of the parasite population. The new vaccine has also been shown to be effective in animals. Tests in blood samples from children in endemic areas showed that the antibodies against this key protein offered improved protection against the disease. Scientists now hope to carry out full-scale human trials. Malaria is spread by mosquito bites and affects people and animals, mostly in sub-Saharan Africa. According to the World Health Organization, in 2009 the disease affected 225 million people and caused an estimated 781,000 deaths, mostly among African children. The new study, published on October 26, 2011 in PLoS ONE, was supported by the European Commission.

October 29th

Gene Expression in Brain Charted Across Lifespan

The “switching on” or expression of specific genes in the human genome is what makes each human tissue and each human being unique. A new study by researchers at the Johns Hopkins Bloomberg School of Public Health, the Lieber Institute for Brain Development, the National Institute of Mental Health, and collaborating institutions has found that many gene expression changes that occur during fetal development are reversed immediately after birth. Reversals of fetal expression changes are also seen again much later in life during normal aging of the brain. Additionally, the team observed the reversal of fetal expression changes in Alzheimer’s disease findings reported in other studies. The research team also found that gene expression change is fastest in human brain tissue during fetal development, slows down through childhood and adolescence, stabilizes in adulthood, and then speeds up again after age 50, with distinct redirection of expression changes prior to birth and in early adulthood. The team’s findings were published in the October 27, 2011 issue of Nature. All of the data is available to the public as a web-based resource at: Using a number of genomic analysis technologies, the research team conducted genome-wide genetic (DNA) and gene expression (RNA) analyses of brain tissue samples from the prefrontal cortex. Tissue represented the various stages of the human lifespan. “We think that these coordinated changes in gene expression connecting fetal development with aging and neurodegeneration are central to how the genome constructs the human brain and how the brain ages,” said Dr. Carlo Colantuoni, one of the lead authors of the study and a former research associate with the Department of Biostatistics at the Johns Hopkins Bloomberg School of Public Health. Dr.

MicroRNA Inhibition May Combat Cardiovascular Disease

A new therapy being studied in non-human primates by researchers at Wake Forest Baptist Medical Center, and colleagues, is demonstrating promise as a potential tool for combating cardiovascular disease by increasing good cholesterol and lowering triglycerides in the blood. Supported by the National Institutes of Health and the Canadian Institutes of Health Research, the preclinical findings were published online on October 19, 2011 in Nature. "The study was conducted because there is a very strong inverse correlation between the amount of HDL (good cholesterol) and heart disease," said co-principal investigator Dr. Ryan Temel, an assistant professor of pathology and lipid sciences at Wake Forest Baptist. "The higher your level of HDL, the lower your risk of developing cardiovascular disease. Currently, however, there are few therapies that significantly raise HDL." While there are several effective therapies available on the market for lowering LDL, or bad cholesterol, modern medicine has yet to find a good way to raise HDL, Dr. Temel said. "Even if you take a statin or some other therapy to lower your LDL, the risk of having coronary heart disease is still around 50 percent. There's clearly a lot of room left for improvement." Dr. Temel and colleagues from the New York University (NYU) Langone Medical Center and Regulus Therapeutics Inc., a biopharmaceutical company, are studying a new drug that targets microRNA-33 (miR-33). MiR-33 is a small RNA molecule that reduces HDL and increases triglyceride production. In previous studies in mice, the drug has been effective in promoting atherosclerotic plaque regression and increasing HDL. For the current study, researchers tested the drug, anti-miR-33, in non-human primates and found that it increased HDL cholesterol and lowered triglycerides.

October 28th

New Discovery May Bring Lung Regeneration Closer to Reality

Researchers at Weill Cornell Medical College, and colleagues, say they have taken an important step forward in their quest to "turn on" lung regeneration -- an advance that could effectively treat millions of people suffering from respiratory disorders. In the October 28, 2011 issue of Cell, the research team reports that they have uncovered the biochemical signals in mice that trigger generation of new lung alveoli, the numerous, tiny, grape-like sacs within the lung where oxygen exchange takes place. Specifically, the regenerative signals originate from the specialized endothelial cells that line the interior of blood vessels in the lung. While it has long been known that mice can regenerate and expand the capacity of one lung if the other is missing, this study now identifies molecular triggers behind this process, and the researchers believe these findings are relevant to humans. "Several adult human organs have the potential upon injury to regenerate to a degree, and while we can readily monitor the pathways involved in the regeneration of liver and bone marrow, it is much more cumbersome to study the regeneration of other adult organs, such as the lung and heart," says the study's lead investigator, Dr. Shahin Rafii, who is the Arthur B. Belfer Professor of Genetic Medicine and co-director of the Ansary Stem Cell Institute at Weill Cornell Medical College. "It is speculated, but not proven, that humans have the potential to regenerate their lung alveoli until they can't anymore, due to smoking, cancer, or other extensive chronic damage," says Dr. Rafii, who is also an investigator of the Howard Hughes Medical Institute.

Genome Studies Reveal Extensive Copy Number Variation in Leishmania Parasites

Two remarkable discoveries have been revealed by researchers analyzing the genomes of Leishmania parasites. The research results were published in two studies appearing online on October 28, 2011 in Genome Research. First, the scientists found that the DNA sequence of individual strains of each species populations is almost completely identical. It appears that only a small number of genes may cause different symptoms of infection. Second, the parasite's evolutionary development and success may be driven by a genetic abnormality leading to multiple copies of chromosomes that would kill most organisms. This process leads to multiple copies of chromosomes and genes known as copy number variation. These studies increase our understanding of the process of drug resistance in Leishmania. Leishmaniasis is a disfiguring and potentially fatal disease that affects two million people each year. There are four main forms of the disease; ranging from skin lesions (cutaneous leishmaniasis), caused by species that include Leishmania mexicana, to a deadly infection of internal organs (visceral leishmaniasis, also called “black fever”) caused by Leishmania donovani parasites. Leishmania parasites are transmitted by sand flies and are found in 88 countries around the world. Leishmaniasis is poverty-related and typically affects the poorest of the poor: it is associated with malnutrition and displacement. The World Health Organization is committed to eradicating the disease in endemic areas. In the first of the two current studies, the researchers generated a high-quality draft genome of L. donovani using a sample taken from an infected patient in Nepal. The team used this as a reference framework to analyse a further 16 isolates from Nepal and India that had different responses to antibiotic medications.

Genetic Risk Factor Identified for Major Depression

Scientists at the Texas Biomedical Research Institute and Yale University have identified a new target area in the human genome that appears to harbor genes with a major role in the onset of depression. Using the power of Texas Biomed’s AT&T Genomics Computing Center (GCC), the researchers found the region by devising a new method for analyzing thousands of potential risk factors for this complex disease, a process that led them to a new biomarker that may be helpful in identifying people at risk for major depression. “We were searching for things in psychiatric disease that are the equivalent of what cholesterol is to heart disease,” said Dr. John Blangero, director of the GCC and a principal investigator in the study. “We wanted to find things that can be measured in everybody and that can tell you something about risk for major depression.” The study was directed by Dr. Blangero and Dr. David Glahn, of Yale University. It was published online on October 7, 2011 in the journal Biological Psychiatry and supported by the National Institutes of Health. Major depressive disorder is one of the most common and most costly mental illnesses. Studies have estimated that up to 17 percent of Americans will suffer depression at some point in their lives. The disorder has proven to be a tough challenge for geneticists. Despite strong evidence that people can inherit a susceptibility to major depression, years of study have failed to locate any of the key genes that underlie the illness. In this study, the scientists used blood samples from 1,122 people enrolled in the Genetics of Brain Structure and Function Study, a large family study that involves people from 40 extended Mexican American families in the San Antonio area. Dr.

New Oncolytic Virus Shows Promise for Treatment of Brain Cancer

A new, fourth-generation oncolytic virus designed to both kill cancer cells and inhibit blood-vessel growth has shown greater effectiveness than earlier versions when tested in animal models of human brain cancer. Researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) are developing the oncolytic virus as a treatment for glioblastoma, the most common and deadly form of brain cancer (average survival: 15 months after diagnosis). The new oncolytic virus, called 34.5ENVE, improved survival of mice with transplanted human glioblastoma tumors by 50 percent in a majority of cases compared with the previous-generation oncolytic virus. The study was published online on October 25, 2011 in the journal Molecular Therapy. “These findings show the amazing therapeutic efficacy of this new oncolytic virus against four different glioblastoma models in animals,” says cancer researcher Dr. Balveen Kaur, associate professor of neurological surgery, and a member of the OSUCCC – James viral oncology research program. The new oncolytic virus is engineered to replicate in cells that express the protein nestin. First identified as a marker for neuronal stem cells, nestin is also expressed in glioblastoma and other malignancies, including gastrointestinal, pancreatic, prostate, and breast cancer. “We believe that nestin-driven oncolytic viruses will prove valuable for the treatment of many types of cancer,” Dr. Kaur says. The new oncolytic virus also carries a gene to inhibit tumor blood-vessel growth. That gene, called Vstat120, was added to increase the virus’s anti-tumor effectiveness and prolong the virus’s presence within tumors.

Scientists Identify Stem Cell Key to Lung Regeneration

Scientists at A*STAR (Agency for Science, Technology, and Research)’s Genome Institute of Singapore (GIS) and Institute of Molecular Biology (IMB), together with colleagues, have made a breakthrough discovery in the understanding of lung regeneration. Their research showed for the first time that distal airway stem cells (DASCs), a specific type of stem cells in the lungs, are involved in forming new alveoli to replace and repair damaged lung tissue, providing a firm foundation for understanding lung regeneration. The new research was reported in the October 28, 2011 issue of Cell. Lung damage is caused by a wide range of lung diseases including influenza infections and chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD). Influenza infection induces acute respiratory distress syndrome (ARDS) which affects more than 150,000 patients a year in the US, with a death rate of up to 50 percent. COPD is the fifth biggest killer worldwide. The research team took a novel approach in tackling the question of lung regeneration. They cloned adult stem cells taken from three different parts of the lungs - nasal epithelial stem cells (NESCs), tracheal airway stem cells (TASCs), and distal airway stem cells (DASCs). Despite the three types of cells being nearly 99 percent genetically identical, the team made the surprising observation that only DASCs formed alveoli when cloned in vitro. "We are the first researchers to demonstrate that adult stem cells are intrinsically committed and will only differentiate into the specific cell type they originated from. In this case, only DASCs formed alveoli because alveolar cells are found in the distal airways, not in the nasal epithelial or tracheal airway," said Dr Wa Xian, Principal Investigator at IMB.