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Archive - May 2012

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May 11th

Long-Lived Naked Mole Rats Have Large Amounts of Key Brain Protein

The typical naked mole rat lives 25 to 30 years, during which time it shows little decline in activity, bone health, reproductive capacity, and cognitive ability. What is the secret to this East African rodent’s long, healthy life? Scientists from the United States and Israel have found a clue. From infancy to old age, naked mole rats are blessed with large amounts of a protein essential for normal brain function. “Naked mole rats have the highest level of a growth factor called NRG-1 (neuregulin 1) in the cerebellum. Its levels are sustained throughout their life, from development through adulthood,” said Yael Edrey, doctoral student at The University of Texas Health Science Center San Antonio’s Barshop Institute for Longevity and Aging Studies. The Barshop Institute has the largest colony of naked mole rats in the U.S. — 2,000 rodents scampering around a network of tubes and cages in humid conditions that mimic their natural underground habitat. Edrey is the lead author of research that compared lifelong NRG-1 levels across seven species of rodents, from mice and guinea pigs to blind mole rats and Damaraland mole rats. NRG-1 levels were monitored in naked mole rats at different ages ranging from 1 day to 26 years. The other six rodent species have maximum life spans of three to 19 years. The cerebellum coordinates movements and maintains bodily equilibrium. The research team hypothesized that long-lived species would maintain higher levels of NRG-1 in this region of the brain, with simultaneous healthy activity levels. Among each of the species, the longest-lived members exhibited the highest lifelong levels of NRG-1. The naked mole rat had the most robust and enduring supply. “In both mice and in humans, NRG-1 levels go down with age,” Edrey said.

Long-Lived Naked Mole Rats Have Unusual Proteasomes

The naked mole rat, a curiously strange, hairless rodent, lives many years longer than any other mouse or rat. Scientists at The University of Texas (UT) Health Science Center San Antonio’s Barshop Institute of Longevity and Aging Studies continue to explore this mystery. On May 2, 2012, a Barshop Institute team reported that the naked mole rat’s cellular machines for protein disposal — called proteasome assemblies — differ in composition from those of other short-lived rodents. The study appeared in the journal PLoS ONE. This is the first report of the molecular mechanisms that underlie the naked mole rat’s superior ability to maintain protein integrity. “More effective removal of damaged proteins within the cell would enable the animal to be able to maintain good function and is likely to contribute to its excellent maintenance of good health well into its third decade of life,” said Rochelle Buffenstein, Ph.D., of the Barshop Institute. Dr. Buffenstein is a professor of physiology and cellular and structural biology in the School of Medicine at the UT Health Science Center. Dr. Buffenstein and her research team reported in 2009 that the naked mole rat maintains exceptional protein integrity throughout its long and healthy life. In the new study, the team found a greater number of proteasomes and higher protein-disposal activity in naked mole rat liver cells. The Barshop Institute scientists, including lead author Karl Rodriguez, Ph.D., postdoctoral fellow, and Yael Edrey, a graduate student, also found large numbers of immunoproteasomes in the liver cells — a bit of a surprise because these protein disposers, which remove antigens after presentation in the immune system, are more commonly found in the spleen and thymus.

May 9th

New Technique Captures MicroRNA Targets

Human cells are thought to produce thousands of different microRNAs (miRNAs)—small pieces of genetic material that help determine which genes are turned on or off at a given time. miRNAs are an important part of normal cellular function, but they can also contribute to human disease—some are elevated in certain tumors, for example, where they promote cell survival. But to better understand how miRNAs influence health and disease, researchers first need to know which miRNAs are acting upon which genes—a big challenge considering their sheer number and the fact that each single miRNA can regulate hundreds of target genes. Enter miR-TRAP, a new easy-to-use method to directly identify miRNA targets in cells. This technique, developed by Tariq Rana, Ph.D., professor and program director at Sanford-Burnham Medical Research Institute (Sanford-Burnham), and his team, was first revealed in a paper published May 8, 2012 by the journal Angewandte Chemie International Edition. "This method could be widely used to discover miRNA targets in any number of disease models, under physiological conditions," Dr. Rana said. "miR-TRAP will help bridge a gap in the RNA field, allowing researchers to better understand diseases like cancer and target their genetic underpinnings to develop new diagnostics and therapeutics. This will become especially important as new high-throughput RNA sequencing technologies increase the numbers of known miRNAs and their targets." miRNAs block gene expression not by attaching directly to the DNA itself, but by binding to messenger RNA (mRNA), the type that normally carries a DNA recipe out of the nucleus and into the cytoplasm, where the sequence is translated into protein. Next, these RNAs are bound by a group of proteins called the RNA-induced silencing complex, or RISC.

Next-Gen Sequencing Used at Duke to Aid Difficult Diagnoses

Advanced high-speed gene-sequencing has been used in the clinical setting to find diagnoses for seven children out of a dozen who were experiencing developmental delays and congenital abnormalities for mysterious reasons. "I thought if we could obtain even a couple of relatively secure diagnoses out of the 12 patients, that would prove the value of deploying sequencing approaches systematically in patients with unknown but apparently genetic conditions," said David Goldstein, Ph.D., director of the Duke Center for Human Genome Variation and professor of molecular genetics and microbiology. "Few sequencing studies have approached the problem as we did, taking a very heterogeneous group of patients," Dr. Goldstein said. "Getting a likely diagnosis about half of the time is quite stunning and strongly motivates next-generation sequencing for all patients who fail to get a genetic diagnosis through traditional testing." The research team used next-generation sequencing, a new technology that can rapidly read a person's entire genome or just their exome, the sections of DNA that make the proteins, which direct physiological activities. The cost of such sequencing is becoming lower, making it feasible to do the study in a clinical setting. The work was published online on May 8, 2012 in the Journal of Medical Genetics. "There are up to 50,000 live births in America each year with the children having features of developmental delays, intellectual disabilities, or congenital abnormalities similar to those we studied," said Vandana Shashi, M.D., co-author and associate professor of pediatrics in the Duke Center for Human Genetics.

May 9th

Antisense Oligo Is Drug Candidate for Human Retinal Neovascular Diseases

Gene Signal, a Swiss company focused on developing innovative drugs to manage angiogenesis-based conditions, announced on May 8, 2012 that positive data from a study of aganirsen (GS-101, eye drops) in a nonhuman primate model of choroidal neovascularization has been presented at the 2012 ARVO Annual Meeting in Fort Lauderdale, Florida. Topical administration of aganirsen was found to inhibit neovascular growth and leakage in this model and strongly suggests a role for the drug candidate in human retinal neovascular diseases such as wet age-related macular degeneration (AMD) and ischemic retinopathy. Gene Signal's aganirsen is an antisense oligonucleotide that is expected to complete a phase III trial for the treatment of progressive neovascularization in the cornea in 2012. Clinical studies in retinal diseases are schedule to begin during the second quarter of 2012. "This study demonstrates the ability of aganirsen to address neovascularization formation in the retina by inhibiting the expression of the angiogenic protein IRS-1. Importantly, this is achieved without affecting normal vascularisation," noted Dr. Matthew Lawrence of RxGen, Inc, who presented the data. "With the demand for new, effective antiangiogenic agents that are easier to use in the treatment of several eye diseases growing, we believe these data strongly support a role for aganirsen." Aganirsen blocks pathological neovascularization by inhibiting IRS-1. Clinical studies to date have shown that aganirsen is able to safely and effectively inhibit the development of progressive corneal neovascularization secondary to infectious keratitis or chemical burns, both of which could lead to corneal graft replacement. "A topical agent for neovascular disease would revolutionize treatment.

May 6th

Orangutans Host Ancient Jumping Genes

Louisiana State University’s Dr. Mark Batzer, along with research associate Dr. Jerilyn Walker and assistant professor Dr. Miriam Konkel, have published research determining that modern-day orangutans are host to ancient jumping genes called Alu, which are more than 16 million years old. The study was done in collaboration with the Zoological Society of San Diego and the Institute of Systems Biology in Seattle and was published online on April 30, 2012 in the new open access journal Mobile DNA. These tiny pieces of mobile DNA are able to copy themselves using a method similar to that of retroviruses. They can be thought of as molecular fossils, as a shared Alu element sequence and location within the genome indicates a common ancestor. But, because this is an inexact process, a segment of “host” DNA is duplicated at the Alu insertion sites and these footprints, known as target site duplications, can be used to identify Alu insertions. “However, it has long been recognized that only a small fraction of these elements retain the ability to mobilize new copies as ‘drivers,’ while most are inactive,” said Dr. Batzer, Boyd Professor and Dr. Mary Lou Applewhite Distinguished Professor of Biological Sciences. “In humans, telling the difference has proven quite difficult, mainly because the human genome is filled with plenty of relatively young Alu insertions, all with slight differences while at the same time lacking easily identifiable features characteristic for Alu propagation. This makes it hard to find their ‘parent’ or ‘source Alu’ from potentially hundreds of candidates that look similar.” In contrast to humans and other studied primates, recent activity of Alu elements in the orangutan has been very slow, with only a handful of recent events by comparison.

May 6th

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 http://personalizedmedicine.sfsu.edu/. 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.

May 4th

Researchers Discover First Gene Linked to Missing Spleen in Newborns

Researchers at Weill Cornell Medical College and Rockefeller University in New York City have identified the first gene to be linked to a rare condition in which babies are born without a spleen, putting those children at risk of dying from infections they cannot defend themselves against. The gene, Nkx2.5, was shown to regulate genesis of the spleen during early development in mice. The study, published online on May 3, 2012 in Developmental Cell, raises the hope that a simple genetic screening test for Nkx2.5 mutations can be developed that will alert parents that their developing child may be missing the organ, which could then be confirmed with a diagnostic scan. "The great news is that with the appropriate preventive antibiotic treatment these children will not succumb to fatal infections. This test could potentially save lives," says the study's lead investigator, Dr. Licia Selleri, an associate professor in the Department of Cell and Developmental Biology at Weill Cornell Medical College. Because defense against infections depends, in part, on the spleen, children known to be born without the organ require treatment with a regimen of antibiotic therapy throughout their lives. But most diagnoses of this condition, congenital asplenia, are made during an autopsy after a child dies, suddenly and unexpectedly, from a rapidly lethal infection, usually from bacteria that causes pneumonia or meningitis, Dr. Selleri says. "For those reasons, we believe this condition is not quite as rare as believed. Not every child who dies from an infection is given an autopsy." Patients with congenital asplenia usually lack a spleen as the sole abnormality, but sometimes have abnormalities of the heart and blood vessels.

Extra Gene Drove Instant Leap in Human Brain Evolution

A partial, duplicated copy of a gene appears to be responsible for the critical features of the human brain that distinguish us from our closest primate kin. The momentous gene duplication event occurred about two or three million years ago, at a critical transition in the evolution of the human lineage, according to a pair of studies published on May 3, 2012 in Cell. The studies are the first to explore the evolutionary history and function of any uniquely human gene duplicate. These "extra" genes are of special interest as they provide likely sources of raw material for adaptive evolutionary change. Until now, studying them has been a technical challenge because they are nearly indistinguishable from each other. "There are approximately 30 genes that were selectively duplicated in humans," said Dr. Franck Polleux, an expert in brain development at The Scripps Research Institute. "These are some of our most recent genomic innovations." Intriguingly, many of these genes appear to play some role in the developing brain. In two independent studies, Dr. Polleux and Dr. Evan Eichler, a genome scientist at the University of Washington, focused their expertise and attention on one of the genes known as SRGAP2. This gene has, in fact, been duplicated at least twice during the course of human evolution, first about 3.5 million years ago and then again about 2.5 million years ago. The new work shows that the second and relatively recent duplication event produced only a partial copy of the gene. This copy acts at exactly the same time and place as the original, allowing it to interact with and block the ancestral gene's function. "This innovation couldn't have happened without that incomplete duplication," Dr. Eichler said.

Beehive Extract Shows Potential As Prostate Cancer Treatment

An over-the-counter natural remedy derived from honeybee hives arrests the growth of prostate cancer cells and tumors in mice, according to a new paper from researchers at the University of Chicago Medicine. Caffeic acid phenethyl ester, or CAPE, is a compound isolated from honeybee hive propolis, the resin used by bees to patch up holes in hives. Propolis has been used for centuries as a natural remedy for conditions ranging from sore throats and allergies to burns and cancer. But the compound has not gained acceptance in the clinic due to scientific questions about its effect on cells. In a paper published in the May 1, 2012 issue of Cancer Prevention Research, researchers combined traditional cancer research methods with cutting-edge proteomics to find that CAPE arrests early-stage prostate cancer by shutting down the tumor cells' system for detecting sources of nutrition. "If you feed CAPE to mice daily, their tumors will stop growing. After several weeks, if you stop the treatment, the tumors will begin to grow again at their original pace," said Richard B. Jones, Ph.D., assistant professor in the Ben May Department for Cancer Research and Institute for Genomics and Systems Biology and senior author of the study. "So it doesn't kill the cancer, but it basically will indefinitely stop prostate cancer proliferation." Natural remedies isolated from plant and animal products are often marketed as cure-alls for a variety of maladies, usually based on vague antioxidant and anti-inflammatory claims. While substances such as ginseng or green tea have been occasionally tested in laboratories for their medicinal properties, scientific evidence is commonly lacking on the full biological effects of these over-the-counter compounds. "It's only recently that people have examined the mechanism by which some of these herbal remedies work," Dr. Jones said.