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Archive - Apr 2012

April 29th

Scripps Scientist Receives $1.5 Million to Use RNA Approach to Design Drugs

A scientist from the Florida campus of The Scripps Research Institute has been awarded $1.5 million from the National Institutes of Health to develop new computer-driven design methods to find new therapeutics targeting RNA. Matthew Disney, Ph.D., an associate professor at Scripps Research, is the principal investigator for the four-year study. RNA was once considered a passive messenger, used only to carry copies of the DNA needed to produce or translate proteins. All that changed when it was found that RNA could produce chemical reactions that, for example, cause proteins to fold into various forms. RNA is an increasingly important potential target for the design of small molecule therapeutics, although methods to design small molecule drugs that bind to RNA and affect its function are still in their infancy. "The rational design of small molecules that exploit therapeutic targets from genomic sequence was one of the promises of the human genome project, but people had no idea of how to do it," Dr. Disney said. "As a result, most targets—especially RNA targets—represent untapped potential." A computer program created by Dr. Disney merges information on the interaction between small molecules (potential drugs) and RNA folds that contribute to specific diseases. Disney said his approach differs from conventional "top-down" methods that normally screen an RNA target against a broad chemical library. "Our bottom-up approach uses information about the small RNA motifs such as internal loops or hairpins that a small molecule ligand prefers to bind," he said. Using this method, Dr. Disney recently successfully designed several small molecules that are strongly active against myotonic dystrophy type 1, the most common form of muscular dystrophy.

Novel Mutations Linked to Autism Identified in Genes Associated with Fragile X

A new study, published in the April 26, 2012 issue of Neuron, reports the discovery of several genes associated with autism and finds evidence for a shared genetic mechanism underlying autism and fragile X syndrome, the most common genetic cause of intellectual disability. It is well established that genetic variation caused by mutation can lead to autism spectrum disorders, and research has repeatedly implicated "de novo" mutations, those that show up for the first time in affected children, as being particularly relevant. Identification of the specific genes associated with autism may lead to much needed advances in the diagnosis and treatment of autism spectrum disorders. The current study, led by Dr. Michael Wigler from Cold Spring Harbor Laboratory, used gene sequencing methods to look at nearly 350 families with healthy children and children on the autistic spectrum, part of the larger Simons Simplex Collection. Specifically, the researchers looked for mutations that were present in the children, but not in their parents. The team found that autism is linked with the types of new mutations that are likely to disrupt the function of a gene. By disrupting one of the pair of healthy genes that we normally inherit, such mutations alter "gene dosage." There was a two-fold higher incidence of such mutations in the affected child than in the healthy child, but little to no difference in the overall incidence of much more prevalent types of mutations. The results also showed that children with older parents have more new mutations. This is consistent with other recent reports and perhaps explains why older parents are more likely to have children on the autism spectrum.

Pig Mucins Are Effective As Anti-Viral Agents for Consumer Products

Scientists are reporting that the mucus lining the stomachs of pigs could be a long-sought, abundant source of "mucins" being considered for use as broad-spectrum anti-viral agents to supplement baby formula and for use in personal hygiene and other consumer products to protect against a range of viral infections. Their study appeared online on April 4, 2012 in the American Chemical Society journal Biomacromolecules. In the report, Dr. Katharina Ribbeck, Eugene Bell Career Development Professor of Tissue Engineering in MIT’s Department of Biological Engineering, and colleagues point out that mucus, which coats the inside of the nose, mouth, and vagina, is the immune system's first line of defense. The slimy secretion traps disease-causing microbes, ranging from influenza virus to HIV (which causes AIDS) before they can cause infection. That has led to consideration of mucin, the main component of mucus, for use as an anti-viral agent in a variety of products. However, existing sources of mucins, such as breast milk, cannot provide industrial-sized quantities. Large amounts of mucus exist in the lining of pigs' stomachs, and the authors set out to determine if pig mucus — already used as a component of artificial saliva to treat patients with "dry mouth," or xerostomia — has the same anti-viral activity. They found that pig mucus is effective at blocking a range of viruses, from strains of influenza to the human papilloma virus, which is associated with cervical and oral cancer. They report that pig mucins could be added to toothpastes, mouthwashes, wound ointments, and genital lubricants to protect against viral infections. "We envision porcine gastric mucins to be promising antiviral components for future biomedical applications," the report says.

April 28th

San Francisco Personalized Medicine Conference 5.0 Will Focus on Epigenetics

The fifth annual Personalized Medicine Conference (5.0) hosted by San Francisco State University, this year with a focus on epigenetics, will be held on Thursday, May 24, 2012 from 8:00 am to 7:30 pm at the South San Francisco Conference Center. To view the conference website and to register for the conference, please go to Scheduled speakers include Michael Snyder, M.D., Ph.D., Chair/Director, Department of Genetics & Stanford Center for Genomics and Personalized Medicine, Stanford University; Brian Kennedy, Ph.D., CEO, Buck Institute for Age Research; Cristina Gentilini, Ph.D., Commercial Research Scientist, Swedish Biomimetics 3000; Jorge A. Leon, President/CEO, Leomics Associates, Inc.; and Stephen M. Anderson, Ph.D., CSO of Oncology and Genetics, LabCorp. The organizers note that epigenetics, or genetic changes above and beyond the DNA sequence level, have profound implications for personalized medicine, pharmacogenomics, aging, and oncology. While personalized medicine is poised to transform healthcare over the next several decades, it has become abundantly clear that the DNA sequence itself is only part of the story. The regulation of gene expression, and how it changes in health and disease, and in response to therapy, are crucial. The organizers invite you to attend this conference and learn the latest information on how epigenetics is and will be impacting personalized medicine. The conference will also be an excellent networking opportunity for health and industry professionals, educators, and scientists. Seating is limited and if you register early, you can save $100 on the registration fee. Sponsors of the conference include Genentech, Celgene, LabCorp, and BioMarin, among many others.

“Single Most Dramatic Improvement in the Treatment of Melanoma in 20 Years"

At Moffitt Cancer Center in Tampa, Florida, patients with stage III and IV unresectable melanoma are now routinely genetically profiled for several gene mutations, including ones in the BRAF gene, a known driver oncogene for melanoma. Research has shown that mutations in the BRAF gene determine sensitivity or resistance to a class of drugs that are BRAF inhibitors. "We have found that a large number of patients with melanoma who have the BRAF gene mutation quickly develop resistance to drugs that are BRAF inhibitors," said Jeffrey S. Weber, M.D., Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt. "A recent approach in the melanoma research community is to find ways to overcome resistance to drugs we targeted to mutated BRAF." At Moffitt, researchers have access to a large database of patient-donated tissues through Moffitt's Total Cancer Care™ program, a far-reaching design for care that includes building a biorepository of tumor samples for study and patient selection for clinical trials participation. By looking for patient genetic profiles for BRAF, Moffitt researchers are working at the frontiers of personalized medicine, which is the effort to match the right patient to the right drug. According to Dr. Weber, although 50 percent of melanoma patients might have the BRAF mutation, the lack of other valid molecular targets for melanoma has "hampered efforts to individualize therapy." That may have changed now that the U.S. Food and Drug Administration has approved the drug Vemurafenib for melanoma patients who test positive for the BRAF mutation. An international team of researchers, including those at Moffitt led by Dr.

April 27th

Mayo Scientists ID Single Gene Driving Most Common Form of Lung Cancer

A single gene that promotes initial development of the most common form of lung cancer and its lethal metastases has been identified in a mouse model by researchers at the Mayo Clinic in Florida. Their study suggests other forms of cancer may also be driven by this gene, matrix metalloproteinase-10 (MMP-10). The study, published in PLoS ONE on April 24, 2012, shows that MMP-10 is a growth factor secreted and then used by cancer stem-like cells to keep themselves vital. These cells then drive lung cancer and its spread, and are notoriously immune to conventional treatment. The findings raise hope for a possible treatment for non-small cell lung cancer, the leading cause of U.S. cancer deaths. Researchers discovered that by shutting down MMP-10, lung cancer stem cells lose their ability to develop tumors. When the gene is given back to the cells, they can form tumors again. The power of this gene is extraordinary, says senior investigator Alan Fields, Ph.D., the Monica Flynn Jacoby Professor of Cancer Research within the Department of Cancer Biology at the Mayo Clinic in Florida. "Our data provides evidence that MMP-10 plays a dual role in cancer. It stimulates the growth of cancer stem cells and stimulates their metastatic potential," he says. "This helps explain an observation that has been seen in cancer stem cells from many tumor types, namely that cancer stem cells appear to be not only the cells that initiate tumors, but also the cells that give rise to metastases." Dr. Fields says the findings were unexpected, for several reasons. The first is that the cancer stem cells express MMP-10 themselves, and use it for their own growth. Most of the known members of the matrix metalloproteinase gene family are expressed in the tumor's microenvironment, the cells and tissue that surround a tumor, he says.

Progress on Understanding Pathology of Deadly Amphibian Fungus

The fungal infection that killed a record number of amphibians worldwide leads to deadly dehydration in frogs in the wild, according to results of a new study. High levels of an aquatic, chytrid fungus called Batrachochytrium dendrobatidis (Bd) disrupt fluid and electrolyte balance in wild frogs, the scientists say, severely depleting the frogs' sodium and potassium levels and causing cardiac arrest and death. Their findings confirm what researchers have seen in carefully controlled lab experiments with the fungus, but San Francisco State University biologist Dr. Vance Vredenburg said the data from wild frogs provides a much better idea of how the disease progresses. "The mode of death discovered in the lab seems to be what's actually happening in the field," he said, "and it's that understanding that is key to doing something about it in the future." Results of the study were published online on April 25, 2012 in the journal PLoS ONE. "Wildlife diseases can be just as devastating to our health and economy as agricultural and human diseases," said Sam Scheiner, NSF program officer for the joint National Science Foundation-National Institutes of Health Ecology and Evolution of Infectious Diseases program, which funded the research. "Bd has been decimating frog and salamander species worldwide, which may fundamentally disrupt natural systems," said Scheiner. "This study is an important advance in our understanding of the disease--a first step in finding a way to reduce its effects." At the heart of the new study are blood samples drawn from mountain yellow-legged frogs by Dr. Vredenburg and colleagues in 2004, as the chytrid epidemic swept through California's Sierra Nevada mountains.

Mirror MicroRNAs Control Multiple Aspects of Brain Function

Our genes control many aspects of who we are — from the color of our hair to our vulnerability to certain diseases — but how are the genes, and consequently the proteins they make, themselves controlled? Researchers have discovered a new group of molecules that control some of the fundamental processes behind memory function and may hold the key to developing new therapies for treating neurodegenerative diseases. The research, led by academics from the UK’s University of Bristol's Schools of Clinical Sciences, Biochemistry and Physiology and Pharmacology and published in the April 27, 2012 issue of the Journal of Biological Chemistry, has revealed a new group of molecules called mirror-microRNAs. MicroRNAs are non-coding genes that often reside within 'junk DNA' and regulate the levels and functions of multiple target proteins — responsible for controlling cellular processes. The study's findings have shown that two microRNA genes with different functions can be produced from the same piece (sequence) of DNA — one is produced from the top strand and another from the bottom complementary 'mirror' strand. Specifically, the research has shown that a single piece of human DNA gives rise to two fully processed microRNA genes that are expressed in the brain and have different and previously unknown functions. One microRNA is expressed in the parts of nerve cells that are known to control memory function and the other microRNA controls the processes that move protein cargos around nerve cells. Dr. James Uney, Professor of Molecular Neuroscience in the University's School of Clinical Sciences, said: "These findings are important as they show that very small changes in miRNA genes will have a dramatic effect on brain function and may influence our memory function or likelihood of developing neurodegenerative diseases.

Scientists Identify Element of GPS in Pigeons

Birds do not need the latest in navigational technology when it comes to flying south for the winter; they come with their own built-in GPS system that uses the Earth’s magnetic field. But just how they detect the magnetic force is still unknown. Researchers at Baylor College of Medicine (BCM) are now closer to answering that question. In a study that was published online in Science on April 26, 2012, Drs. Le-Qing Wu, post-doctoral fellow, and J. David Dickman, professor of neuroscience, both at BCM, have shown how certain brain cells in pigeons encode the direction and intensity of the Earth’s magnetic field. "We know birds and many other animals can sense the magnetic force; behavioral studies show that birds fly along magnetic routes during seasonal changes," said Dr. Dickman, who conducted much of the research while at Washington University in St. Louis. "It is still unknown what exactly acts as a receptor within the bird; however, in our current study we are able to show how neurons in the pigeon’s brain encode magnetic field direction and intensity. This is how we believe birds know their position on the surface of the Earth." Dr. Dickman said certain areas of the brain are activated when a particular area of the inner ear, known as the lagena, is exposed to a magnetic field. Without it, several of these corresponding areas in the brain show no activity. Drs. Dickman and Wu used electrodes in one brain area, known as the vestibular nuclei, to record activity when the bird was exposed to a changing magnetic field. "The cells responded to the angle and intensity of the magnetic field. Some cells were more sensitive depending on what direction we aimed the magnetic field around the bird’s head," Dr. Dickman said.

April 26th

Discovery of Small Molecules That Kill Cancers Caused by HPV

Researchers at The Wistar Institute in Philadelphia, Pennsylvania, have announced the discovery of small molecules that kill cancer cells caused by infection with human papillomavirus (HPV). Their results, in both cell and mouse models, demonstrate that the small molecule inhibitors protect a tumor-suppressing protein targeted by viral proteins, thus killing the infected tumor cells. The Wistar scientists presented their findings in the April 20, 2012 issue of Chemistry & Biology. The researchers believe that, with further testing and refinement, their inhibitors could provide a therapeutic for HPV-caused tumors, such as those seen in cervical cancer. “While there is an effective vaccine for preventing HPV infection, there is currently no therapeutic that specifically targets cancers caused by the virus,” said Ronen Marmorstein, Ph.D., senior author, Hilary Koprowski, M.D. Professor, and leader of The Wistar Institute Cancer Center’s Gene Expression and Regulation program. “HPV often turns cells cancerous for the virus’s own reproductive advantage, and we have found a class of small molecules that effectively prevents a key HPV protein from allowing cells to become cancerous,” Dr. Marmorstein said. “We think that this could be the start of an effective drug strategy for cancers caused by HPV.” HPV is one of the primary infectious causes of cancer, responsible for most cases of cervical cancer, nearly 20 percent of all head and neck cancers, and has been implicated in cancers of the vagina, penis, and anus. American Cancer Society statistics estimate that over 4,000 women will die this year from cervical cancer alone. The U.S. Centers for Disease Control estimate that about 50 percent of sexually active men and women will be infected with HPV at one point in their lives.