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March 4th, 2014

Loss-of-Function Mutations in Key Gene Protect Against Type 2 Diabetes

An international team led by researchers at the Broad Institute and Massachusetts General Hospital (MGH) has identified mutations in a gene that can reduce the risk of developing type 2 diabetes, even in people who have risk factors such as obesity and old age. The results focus the search for developing novel therapeutic strategies for type 2 diabetes; if a drug can be developed that mimics the protective effect of these mutations, it could open up new ways of preventing this devastating disease. Type 2 diabetes affects over 300 million people worldwide and is rising rapidly in prevalence. Lifestyle changes and existing medicines slow the progression of the disease, but many patients are inadequately served by current treatments. The first step to developing a new therapy is discovering and validating a “drug target” — a human protein that, if activated or inhibited, results in prevention and treatment of the disease. The current study breaks new ground in type 2 diabetes research and guides future therapeutic development in this disease. In the new study, researchers describe the genetic analysis of 150,000 patients showing that rare mutations in a gene called SLC30A8 reduce the risk of type 2 diabetes by 65 percent. The results were seen in patients from multiple ethnic groups, suggesting that a drug that mimics the effect of these mutations might have broad utility around the globe. The protein encoded by SLC30A8 had previously been shown to play an important role in the insulin-secreting beta cells of the pancreas, and a common variant in that gene was known to slightly influence the risk of type 2 diabetes. However, it was previously unclear whether inhibiting or activating the protein would be the best strategy for reducing disease risk — and how large an effect could be expected.

30,000-Year-Old Giant Virus Found in Siberia

A new type of giant virus called "Pithovirus" has been discovered in the frozen ground of extreme north-eastern Siberia by researchers from the Information Génomique et Structurale laboratory (CNRS/AMU), in association with teams from the Biologie à Grande Echelle laboratory (CEA/INSERM/Université Joseph Fourier), Génoscope (CEA/CNRS), and the Russian Academy of Sciences. Buried underground, this giant virus, which is harmless to humans and animals, has survived being frozen for more than 30,000 years. Although its size and amphora shape are reminiscent of Pandoravirus, analysis of its genome and replication mechanism proves that Pithovirus is very different. This work brings to three the number of distinct families of giant viruses. The discovery was reported online on March 3, 2014 in PNAS. In the families Megaviridae (represented in particular by Mimivirus, discovered in 2003) and Pandoraviridae, researchers thought they had classified the diversity of giant viruses (the only viruses visible under optical microscopy, because their diameter exceeds 0.5 microns). These viruses, which infect amoeba such as Acanthamoeba, contain a very large number of genes compared to common viruses (like influenza or AIDS, which only contain about ten genes). Their genome is about the same size or even larger than that of many bacteria. By studying a sample from the frozen ground of extreme north-eastern Siberia, in the Chukotka autonomous region, researchers were surprised to discover a new giant virus more than 30,000 years old (contemporaneous with the extinction of Neanderthal man), which they have named "Pithovirus sibericum." Because of its amphora shape, similar to Pandoravirus, the scientists initially thought that this was a new member - albeit certainly ancient - of this family.

February 6th

Giant Protein on Mutant Staph aureus Surface Hinders Clumping and Reduces Ability to Cause Disease

A genetic mechanism that controls the production of a large spike-like protein (the Giant Staphylococcal Surface Protein [GSSP])on the surface of Staphylococcus aureus(staph) bacteria alters the ability of the bacteria to form clumps and to cause disease, according to a new University of Iowa (UI) study. The new study is the first to link this genetic mechanism to the production of the giant surface protein and to clumping behavior in bacteria. It is also the first time that clumping behavior has been associated with endocarditis, a serious infection of heart valves that kills 20,000 Americans each year. The findings were published in the December 2103 issue of the open-access journal PLOS Pathogens. Under normal conditions, staph bacteria interact with proteins in human blood to form aggregates, or clumps. This clumping behavior has been associated with pathogenesis -- the ability of bacteria to cause disease. However, the mechanisms that control clumping are not well understood. In the process of investigating how staph bacteria regulate cell-to-cell interactions, researchers at the UI Carver College of Medicine discovered a mutant strain of staph that does not clump at all in the presence of blood proteins. Further investigation revealed that the clumping defect is due to disruption of a genetic signaling mechanism used by bacteria to sense and respond to their environment. The study shows that when the mechanism is disrupted, the giant surface protein is overproduced -- giving the cells a spiny, or "porcupine-like" appearance -- and the bacteria lose their ability to form clumps.

Rett Syndrome Genetic Variants Now Available for Advance Testing, Diagnosis, and Research

Despite the identification of gene mutations in methyl CpG binding protein 2 (MECP2) being linked to Rett syndrome (RS), research has been hindered by the lack of commercially available reference materials. Through collaboration between the Centers for Disease Control and Prevention (CDC) and members of the clinical-laboratory and non-profit–research communities, 35 DNA samples containing many common RS genetic variants have now been characterized and made publicly available, eliminating a major stumbling-block for investigators and opening the possibility of earlier, more accurate diagnosis of Rett syndrome, reports The Journal of Molecular Diagnostics. The study was conducted via the CDC Genetic Testing Reference Materials Coordination Program (GeT-RM), which aims to help the genetic testing community obtain appropriate and well-defined reference materials for inherited genetic disorders, including cancer and infectious diseases. Researchers selected eight cell lines from RS patients already available from the National Institute of General Medical Sciences' Coriell Cell Repository, which contained six of the most common mutations that cause RS, as well as one additional point mutation. In addition, DNA was obtained from 27 newly established cell lines derived from blood samples from Rett patients, which included a number of other MECP2 variants. Two of the samples were from males. The samples were sent for DNA sequence and deletion/duplication analyses (using MLPA, semi-quantitative PCR, or array) to College of American Pathologist–accredited clinical genetic testing laboratories, and each sample was tested in between two to five laboratories. The investigators found that the results were concordant among laboratories and assay platforms.

February 4th

Smooth Horse Gaits Controlled by Gene Mutation Spread Around the World

From the Faroe Pony to the Spanish Mustang, fewer animals have played such a central role in human history as the horse. New research published online on January 21, 2014 in an open-access article in Animal Genetics reveals that a horse's gait, an attribute central to its importance to humans, is influenced by a genetic mutation, spread by humans across the world. The research team, led by Dr. Leif Andersson from the Swedish University of Agricultural Sciences, explored the distribution of a mutation in the DMRT3 gene which affects the gait of horses, known as the 'gait keeper’ mutation. "All over the world, horses have been used for everyday transportation, in military settings, cattle herding, and agricultural power, pulling carriages and carts, pleasure riding, or racing," said Dr. Andersson. "Over the centuries, horse populations and breeds have been shaped by humans based on the different purposes for which the animals were used." The DMRT3 gene is central to the utility of horses to humans, as it controls a range of gaits as well as pace. From racing to pleasure riding, many species have been bred to encourage smoothness of gait. "For example, the Paso Fino (image) is a breed from Latin America in which the frequency of the 'gait keeper' mutation is nearly 100%. It is claimed that the Paso Fino is so smooth that you can have a glass of wine in your hand without letting it spill," said Dr. Andersson. The team analyzed 4,396 horses from 141 breeds around the world and found that the 'gait keeper' mutation is spread across Eurasia from Japan in the East, to the British Isles in West, on Iceland, in both South and North America, and also in breeds from South Africa.

Scientists Unravel 10-Gene Pathway of Sulpho-Glucose Degradation

By discovering sulpho-glycolysis, researchers of the University of Konstanz have revealed an important degradation pathway. Similarly to the sugar glucose, its sulphurous analogue sulpho-glucose is produced by all photosynthetically active organisms. The annual production of sulpho-glucose in nature is estimated at approximately ten billion tons. Researchers of the Department of Biology of the University of Konstanz, in Germany, led by the microbiologists Dr. David Schleheck and Professor Dr. Alasdair Cook, and supported by colleagues from the Department of Chemistry, have now revealed how sulpho-glucose is degraded. The scientists could identify one degradation pathway in the bacterium Escherichia coli (image), the most widely studied bacterial model organism: the sulpho-glycolytic pathway, encoded by ten genes, whose function had remained unknown thus far. The results have now been published in the online edition of Nature. Sulpho-glucose is present in all plants, mosses, ferns, and algae. The degradation pathway, or metabolic pathway, for sulpho-glucose, sulpho-glycolysis, is therefore an important component of the material cycles in ecosystems. As sulpho-glucose is not commercially available, Dr. Thomas Huhn of the neighboring Department of Chemistry synthesised this special form of sugar in sufficient amounts and purity for study. The analytical-chemical studies to give proof of intermediates were conducted via modern mass spectrometry by the doctoral student Alexander Schneider and the chemists Profesor Dr. Christoph Mayer, now at the University of Tübingen, and Professor Dr. Dieter Spiteller. "The excellent collaboration between biologists and chemists was an important aspect of our work.

NIH Announces $230 Million "AMP" Partnership with Big Pharma to Accelerate Drug Development

On Tuesday, February 4, 2014, The National Institutes of Health (NIH) announced the launch of the Accelerating Medicines Partnership (AMP), an innovative public-private collaboration developed with guidance from The Boston Consulting Group (BCG) over the last year and a half. AMP is the first systematic investment in understanding the biology of difficult-to-treat diseases that was designed from the start by industry, academic, and government partners working together. "Currently, we are investing too much money and time in avenues that don't pan out while patients and their families wait," said NIH director Francis S. Collins, M.D., Ph.D. (image). "All sectors of the biomedical enterprise agree that this challenge is beyond the scope of any one sector, and it's time to work together in new ways to increase our collective odds of success." AMP -- cofounded by the NIH, ten leading pharmaceutical companies, and a number of nonprofit organizations -- will invest $230 million over five years to support the large-scale characterization of the underlying pathology of Alzheimer's disease, type 2 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. BCG was pleased to have supported AMP's initial conception, organization design, and detailed research plans for each of the diseases targeted. "Too many hoped-for drugs fail during R&D, and the reason for this is that we don't fundamentally understand the biology we're trying to modify," said Michael Ringel, J.D., Ph.D., a BCG partner and co-leader of the firm's team facilitating the partnership.

February 3rd

Mood-Stabilizing Drug Could Treat Inherited Liver Disease, Study Finds

In a study published online on January 31, 2014 in the open-access journal PLOS ONE, researchers from Children's Hospital of Pittsburgh of the UPMC and the University of Pittsburgh (Pitt) School of Medicine (UPMC) used a primitive worm model to show that a drug typically used to treat agitation in schizophrenia and dementia has potential as a treatment for alpha-1 antitrypsin (AT) deficiency, an inherited disease that causes severe liver scarring. In the classic form of AT deficiency, which affects 1 in 3,000 live births, a gene mutation leads to production of an abnormal protein, dubbed ATZ, that, unlike its normal counterpart, is prone to clumping, explained David H. Perlmutter, M.D., physician-in-chief and scientific director, Children's Hospital of Pittsburgh, and Distinguished Professor and Vira I. Heinz Endowed Chair, Department of Pediatrics, UPMC. "These protein aggregates accumulate in liver cells and eventually lead to scarring of the organ or to tumor formation," Dr. Perlmutter said. "If we could find a drug that slows or stops this process, we might be able to prevent the need for liver transplantation in these patients." To find that drug, Dr. Perlmutter's team worked with Pitt's Stephen Pak, Ph.D., assistant professor of pediatrics, and Gary Silverman, M.D., Ph.D., Twenty-Five Club Professor of Pediatrics, Cell Biology and Physiology, who developed a model of AT deficiency in Caenorhabditis elegans, or C. elegans, a harmless microscopic worm or nematode typically found in soil. Previous experiments conducted by Drs. Pak and Silverman, in which more than 2,000 compounds were screened, showed that fluphenazine, a drug approved for human use as a mood stabilizer, could reduce ATZ accumulation in the worm, so the team studied it further.

IDH1 Gene Mutation Defines Brain Tumors That Benefit from Aggressive Surgery; Longer Lifespans Support Molecular Genetics Approach

Astrocytomas are the most common malignant brain tumors. While most patients' tumors prove to be quite aggressive, outcomes overall can vary widely, with some patients surviving for many years. Now a new study has found that malignant astrocytoma patients whose tumors carry a specific genetic mutation benefit greatly from surgical removal of the largest possible amount of tumor. Preliminary results of the study were reported at the 2012 American Society of Clinical Oncology meeting, and the team's full report appears in the January 2014 issue of the journal Neuro-Oncology. A type of glioma, astrocytomas include the highly aggressive glioblastoma and the less aggressive, but still dangerous anaplastic astrocytoma. "We found that the benefit of surgery and how aggressively the surgery should be done depend, in large part, on whether or not patients' tumors have the mutated form of the IDH1 gene," says Daniel Cahill, M.D., Ph.D., of the Pappas Center for Neuro-Oncology in the Massachusetts General Hospital (MGH) Cancer Center, who led the study. "Under the prior system of categorization, these tumors were considered the same diagnosis and were treated the same way; but we have found that this mutation identifies a completely different subclass of glioma that probably should be treated differently." Now an assistant professor of Neurosurgery at Harvard Medical School, Dr. Cahill was at the University of Texas MD Anderson Cancer Center when the study was initiated, and all study participants were treated at MD Anderson. Ian McCutcheon, M.D., professor of Neurosurgery at the MD Anderson Cancer Center, who co-led the study with Dr.

Enhancing “Grasp” Gene Function Could Offer New Avenue to Cancer Therapies

Researchers at Oregon State University (OSU) and Oregon Health & Science University have discovered a genetic function that helps one of the most important “tumor suppressor” genes (p53) to do its job and prevent cancer. Finding ways to maintain or increase the effectiveness of this gene function – attributable to a gene is called Grp1-associated scaffold protein, or Grasp – could offer an important new avenue for human cancer therapies, scientists said. The findings were published online on January 6, 2014 in Photochemical and Photobiological Sciences, a journal of the Royal Society of Chemistry. The Grasp gene was studied in the skin of mice in this research, but is actually expressed at the highest levels in the brain, heart, and lung, studies have shown. It appears to play a fundamental role in the operation of the p53 tumor suppressor gene, which is a focus of much modern cancer research. The p53 gene is involved in repair of DNA damage and, if the damage is too great, causing a mutated cell to die before it can cause further problems, up to and including cancer. Dysfunction of p53 genetic pathways have been linked to more than half of all known cancers - particularly skin, esophageal, colon, pancreatic, lung, ovarian, and head and neck cancers. “DNA mutations occur constantly in our bodies just by ordinary stresses, something as simple as exposure to sunlight for a few seconds,” said Dr. Mark Leid, professor of pharmacology and associate dean for research in the OSU College of Pharmacy, and one of the lead authors on this study. “Just as constantly, the p53 gene and other tumor suppressors are activated to repair that damage,” Dr. Leid said. “And in cases where the damage is too severe to be repaired, p53 will cause the apoptosis, or death of the mutated cell.