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October 5th, 2014

New Antibiotic Approach Harnesses Cas9 Enzyme to Specifically Attack Drug-Resistant Microbes

The multitude of microbes scientists have found populating the human body have good, bad, and mostly mysterious implications for our health. But when something goes wrong, we defend ourselves with the undiscriminating brute force of traditional antibiotics, which wipe out everything at once, regardless of the consequences. Researchers at Rockefeller University and their collaborators are working on a smarter antibiotic. And in research published online on October 5, 2014 in Nature Biotechnology, the team describes a “programmable” antibiotic technique that selectively targets the bad microbes, particularly those harboring antibiotic-resistance genes, while leaving other, more innocent microbes alone. "In experiments, we succeeded in instructing a bacterial enzyme, known as Cas9, to target a particular DNA sequence and cut it up," says lead researcher Dr. Luciano Marraffini, head of the Rockefeller’s Laboratory of Bacteriology. "This selective approach leaves the healthy microbial community intact, and our experiments suggest that by doing so you can keep resistance in check and so prevent certain types of secondary infections, eliminating two serious hazards associated with treatment by classical antibiotics." The new approach could, for instance, reduce the risk of C. diff, a severe infection of the colon, caused by the Clostridium difficile bacterium that is associated with prolonged courses of harsh antibiotics and is a growing public health concern. The Cas9 enzyme is part of a defense system that bacteria use to protect themselves against viruses. The team coopted this bacterial version of an immune system, known as a CRISPR (clustered regularly interspaced short palindromic repeats) system and turned it against some of the microbes.

Largest-Ever GWAS Study Doubles Number of Genes Linked to Height to Over 400

The largest genome-wide association study (GWAS) to date, involving more than 300 institutions and more than 250,000 subjects, roughly doubles the number of known gene regions influencing height to more than 400. The study, from the international Genetic Investigation of Anthropometric Traits (GIANT) Consortium, provides a better glimpse at the biology of height and offers a model for investigating traits and diseases caused by many common gene changes acting together. The findings were published online on October 5, 2014 in Nature Genetics. "Height is almost completely determined by genetics, but our earlier studies were only able to explain about 10 percent of this genetic influence," says Joel Hirschhorn, M.D., Ph.D., of Boston Children's Hospital and the Broad Institute of MIT and Harvard, leader of the GIANT Consortium and co-senior investigator on the study. "Now, by doubling the number of people in our study, we have a much more complete picture of how common genetic variants affect height—how many of them there are and how much they contribute." The GIANT investigators, numbering in the hundreds, shared and analyzed data from the genomes of 253,288 people. They checked about two million common genetic variants (those that showed up in at least 5 percent of their subjects). From this pool, they pinned down 697 (in 424 gene regions) as being related to height, the largest number to date associated with any trait or disease. "We can now explain about 20 percent of the heritability of height, up from about 12 percent where we were before," says co-first author Tonu Esko, Ph.D., of Boston Children's Hospital, the Broad Institute, and the University of Tartu (Estonia).

October 4th

Genetic Test Indicates Risk of Atrial Fibrillation and Stroke

Many of those who are genetically predisposed to develop atrial fibrillation, which dramatically raises the risk of stroke, can be identified with a blood test. This has just been shown by new research from Lund University in Sweden. The number of people affected by atrial fibrillation is rising rapidly, partly as a result of the aging population. Over recent years, a research group at Lund University in Sweden, working with other universities and hospitals in Europe and the United States, has identified twelve genetic variants in the human genome that increase the risk of atrial fibrillation. The research group has now studied the possible clinical benefits of a DNA test: "One in five people has a genetic weakness that means they have twice as high a risk of developing atrial fibrillation as those with a low genetic risk. This genetic risk is therefore one of the strongest risk factors for atrial fibrillation that we know of in people without overt cardiac disease. It increases the risk as much as high blood pressure, for example," said Dr. Olle Melander, Professor of Internal Medicine, and Dr. Gustav Smith, Associate Professor in Cardiology, both from Lund University. Because the symptoms of atrial flutter can be weak and unclear, they are sometimes difficult to pick up. However, even those with weak or absent symptoms of atrial flutter are at significantly higher risk of stroke. "In patients who are suspected of having temporary, but recurrent, episodes of atrial fibrillation, or in people with high blood pressure, it can be important for doctors to look at their genetic predisposition using a blood test. The test can give guidance as to how often and how intensively doctors need to screen for presence of atrial fibrillation in these individuals.

Cattle Genome Variation Mapped in Unprecedented Detail

By creating a global database, an international consortium of scientists has increased the detailed knowledge of the variation in the cattle genome by several orders of magnitude. The first generation of the new data resource, which will be open access, forms an essential tool for scientists working with cattle genetics and livestock history. The results are published in as the cover story (image) of the August 2014 issue of Nature Genetics. It's momentous, says one of the scientists behind the international effort, associate professor Dr. Bernt Guldbrandtsen from the Center for Quantitative Genetics and Genomics, Department of Molecular Biology and Genetics, Aarhus University, Denmark. Scientists from Aarhus University – the only Danish university to participate – have been part of the consortium from the start and have contributed 15 percent of the data. The data used in the huge database are derived from key ancestor bulls. These bulls have produced millions of descendants and have had enormous influence on the genetic composition and characteristics of modern cattle breeds. For example, Holstein bulls in the database have fathered at least 6.3 million daughters worldwide. The data consist of sequenced genomes for a number of bulls and are based on new sequencing techniques. The article in Nature Genetics describes data from 232 bulls and 2 cows of the breeds Angus, Holstein, Jersey, and Fleckvieh. Because these animals are key ancestors, they carry most of the genetic variations present in the three races. Currently, the database contains genomes of more than 1,200 animals of different cattle breeds, but as more scientists from other countries gradually join the project, there is a continual influx of data.

Viral Infection in Utero May Trigger Type 1 Diabetes; Seasonality and Winter Epidemics Seem to Be Factors

The incidence of type 1 childhood diabetes has been increasing rapidly worldwide. If blood sugar levels aren't well-controlled, juvenile diabetes can affect nearly every organ of a child's body. And while long-term complications of the disease develop gradually, they may become disabling and even life-threatening. The exact cause of juvenile diabetes has eluded scientists, but a new study from Tel Aviv University (TAU) in Israel suggests a likely pre-birth trigge. In an article published in the June 2014 issue of Diabetic Medicine, Professor Zvi Laron, Professor Emeritus of Pediatric Endocrinology at TAU's Sackler Faculty of Medicine, Director of the Endocrinology and Diabetes Research Unit at Schneider Children's Medical Center of Israel, and Head of the WHO Collaborating Center for the Study of Diabetes in Youth, puts forth evidence that the autoimmune disease is initiated in utero. According to the research, conducted in collaboration with an international team of researchers, women who contract a viral infection during pregnancy transmit viruses to their genetically susceptible fetuses, sparking the development of type 1 diabetes. Professor Laron is internationally known for the discovery of the Laron Syndrome, also known as Laron-Type Dwarfism, an autosomal recessive disorder characterized by an insensitivity to growth hormone. "We knew that type 1 diabetes was associated with other autoimmune diseases like Hashimoto thyroiditis, celiac disease, and multiple sclerosis, so we investigated the seasonality of birth months for these respective diseases in Israel and other countries," said Professor Laron. "We found that the seasonality of the birth of children who went on to develop these diseases did indeed differ from that of the general public.

RCas9 Is a Programmable RNA Editing Tool, New Nature Article Says

A powerful scientific tool for editing the DNA instructions in a genome can now also be applied to RNA, the molecule that translates DNA’s genetic instructions into the production of proteins. A team of researchers with Berkeley Lab and the University of California (UC) Berkeley has demonstrated a means by which the CRISPR/Cas9 protein complex can be programmed to recognize and cleave RNA at sequence-specific target sites. This finding has the potential to transform the study of RNA function by paving the way for direct RNA transcript detection, analysis, and manipulation. Led by Dr. Jennifer Doudna (photo), biochemist and a leading authority on the CRISPR/Cas9 complex, the Berkeley team showed how the Cas9 enzyme can work with short DNA sequences known as “PAM,” for protospacer adjacent motif, to identify and bind with specific sites of single-stranded RNA (ssRNA). The team is designating this RNA-targeting CRISPR/Cas9 complex as RCas9. “Using specially designed PAM-presenting oligonucleotides, or PAMmers, RCas9 can be specifically directed to bind or cut RNA targets while avoiding corresponding DNA sequences, or it can be used to isolate specific endogenous messenger RNA from cells,” says Dr. Doudna, who holds joint appointments with Berkeley Lab’s Physical Biosciences Division and UC Berkeley’s Department of Molecular and Cell Biology and Department of Chemistry, and is also an investigator with the Howard Hughes Medical Institute (HHMI).

Review Questions Advisability of Aggressive Treatment with High Doses and Long Duration to Stem Emergence & Spread of Resistant Pathogens

In response to the rise of drug-resistant pathogens, doctors are routinely cautioned against overprescribing antimicrobials. But when a patient has a confirmed bacterial infection, the advice is to treat aggressively to quash the infection before the bacteria can develop resistance. A new study questions the accepted wisdom that aggressive treatment with high drug dosages and long durations is always the best way to stem the emergence and spread of resistant pathogens. The review of nearly 70 studies of antimicrobial resistance, which was authored by researchers at Princeton and other leading institutions, and published online in an open-access article on September 24, 2014 in the journal Proceedings of the Royal Society B, reveals the lack of evidence behind the practice of aggressive treatment in many cases. The article was entitled, “The Path of Least Resistance: Aggressive or Moderate Treatment?” "We found that while there are many studies that test for resistance emergence between different drug regimens, surprisingly few have looked at the topic of how varying drug dosage might affect the emergence and spread of resistance," said Ruthie Birger, a Princeton graduate student who works with Dr. C. Jessica Metcalf, an assistant professor of ecology and evolutionary biology and public affairs at Princeton's Woodrow Wilson School, and Dr. Bryan Grenfell, the Kathryn Briger and Sarah Fenton Professor of Ecology and Evolutionary Biology and Public Affairs in Princeton's Woodrow Wilson School. Birger, Drs. Metcalf and Grenfell coauthored the paper with colleagues from 16 universities. "We are a long way from having the evidence for the best treatment decisions with respect to resistance for a range of diseases," Dr. Birger said.

October 3rd

NIH Announces $46 Million Initial Funding of BRAIN Initiative

On September 30, 2014, The National Institutes of Health (NIH) announced its first wave of investments totaling $46 million in fiscal year 2014 funds to support the goals of the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. More than 100 investigators in 15 states and several countries will work to develop new tools and technologies to understand neural circuit function and capture a dynamic view of the brain in action. These new tools and this deeper understanding will ultimately catalyze new treatments and cures for devastating brain disorders and diseases that are estimated by the World Health Organization to affect more than one billion people worldwide. “The human brain is the most complicated biological structure in the known universe. We’ve only just scratched the surface in understanding how it works — or, unfortunately, doesn’t quite work when disorders and disease occur,” said NIH Director Francis S. Collins, M.D., Ph.D. “There’s a big gap between what we want to do in brain research and the technologies available to make exploration possible. These initial awards are part of a 12-year scientific plan focused on developing the tools and technologies needed to make the next leap in understanding the brain. This is just the beginning of an ambitious journey and we’re excited about the possibilities.” Creating a wearable scanner to image the human brain in motion, using lasers to guide nerve cell firing, recording the entire nervous system in action, stimulating specific circuits with radio waves, and identifying complex circuits with DNA barcodes are among the 58 projects announced today.

Complex Three-Way Interaction between the Non-Integrin Laminin Receptor, Galectin-3, and Life-Threatening Neisseria meningitides

Previously undiscovered secrets of how human cells interact with a bacterium which causes a serious human disease have been revealed in new research by microbiologists at The University of Nottingham. The scientists at the University’s Centre for Biomolecular Sciences have shed new light on how two proteins found on many human cells are targeted by the human pathogen Neisseria meningitidis (image) which can cause life-threatening meningitis and septicemia. The proteins, laminin receptor 1 (LAMR1) and galectin-3 (Gal-3) are found in and on the surface of many human cells. Previous research has shown that they play diverse roles in a variety of infectious and non-infectious diseases. For example, the LAMR1 is a key receptor targeted by disease-causing pathogens and their toxins and is also a receptor for the spread of cancer around the body and for the development of Alzheimer’s. Using the latest bimolecular fluorescence and confocal imaging techniques, the researchers have shown that these two separate proteins can form pairs made up of two similar molecules (homodimers) or one of each molecule (heterodimers) which are targeted by Neisseria meningitidis. They have also identified critical components which cause the formation of these pairs of molecules. These new mechanistic insights into the three-way relationship between proteins and bacterial pathogens could have significant implications in the fields of infection, vaccination, and cancer biology. Associate Professor of Microbiology, Dr. Karl Wooldridge, said: “We have shown evidence for the self and mutual association of these two important proteins and their distinctive surface distribution on the human cell. We’ve also demonstrated that they are targeted by the serious human pathogen Neisseria meningitidis.

October 2nd

Advanced LC-MS 'Omics Analysis Software for Proteomics Applications Is More Rapid and Reliable Than Ever, Waters Claims

On June 16, 2014, Waters Corporation (NYSE:WAT) unveiled Progenesis® QI for proteomics Version 2.0, the latest advance in proteomics data analysis software, which the company believes enables more rapid and reliable quantification and identification of differentially changing proteins in laboratory samples than ever before. The release of Progenesis QI for proteomics Version 2.0 expands Waters’® suite of focused, world-leading informatics packages for 'omics data analysis. The new features of Progenesis QI for proteomics Version 2.0 include Pathway Analysis, which aids the biological understanding of observed MS data; QC Metrics, which assesses LC-MS data quality to facilitate exclusion of sub-optimal measurements; and Process Automation, which eliminates the need to program repetitive steps to make analysis even faster. The new software now allows user-selectable HiN quantification of proteins, along with full HiN functionality for 2D-LC experiments. Progenesis QI for proteomics Version 2.0 takes ‘omics-based data analysis to the next level by enabling users to rapidly quantify and identify differences between protein samples. It provides an easy-to-learn, intuitive process based on how researchers work, a flexible workflow, and a highly visual interface to give the user confidence in their data. “Progenesis QI for proteomics Version 2.0 gives users more control and functionality than ever before. It solves a major bottleneck for biological research,” said Dr. Rohit Khanna, Vice President of Worldwide Marketing and Informatics for the Waters Division. “The expanded functionality has broad applications across proteomics research, health sciences, and food research.