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Archive - 2012

November 18th

Stanford/Yale Study Gives Insight into Subtle Genomic Differences Among Our Own Cells

Stanford University School of Medicine scientists have demonstrated, in a study conducted jointly with researchers at Yale University, that induced-pluripotent stem cells (iPS cells) — the embryonic-stem-cell lookalikes whose discovery a few years ago won this year's Nobel Prize in medicine — are not as genetically unstable as was thought. The new study, which was published online on Novenber 18, 2012 in Nature, showed that what seemed to be changes in iPS cells' genetic makeup — presumed to be inflicted either in the course of their generation from adult cells or during their propagation and maintenance in laboratory culture dishes — instead are often accurate reflections of existing but previously undetected genetic variations among the cells comprising our bodies. That's good news for researchers hoping to use the cells to study disease or, someday, for regenerative medicine. But it raises the question of whether and to what extent we humans are really walking mosaics whose constituent cells differ genetically from one to the next in possibly significant respects, said Alexander Urban, Ph.D., assistant professor of psychiatry and behavioral sciences at Stanford. Dr. Urban shared senior authorship of the study with bioinformatics professor Mark Gerstein, Ph.D., and neurobiology professor Flora Vaccarino, M.D., both of Yale. It's only a few years ago that human iPS cells started becoming available to researchers. These cells hold great promise because they act almost exactly like embryonic stem cells, which can be nudged to differentiate into virtually any of the body's roughly 200 different cell types. But iPS cells can be derived easily from a person's skin, alleviating numerous ethical concerns arising from the necessity of obtaining embryonic stem cells from fertilized eggs.

Variants of TREM2 Gene Nearly Triple Risk of Alzheimer's

A gene so powerful it nearly triples the risk of Alzheimer's disease has been discovered by an international team including researchers from the Mayo Clinic. It is the most potent genetic risk factor for Alzheimer's identified in the past 20 years. The findings were reported November 14, 2012 in the online edition of the New England Journal of Medicine. The team included researchers from 44 institutions around the world, including 10 from the Mayo Clinic's campuses in Florida and Minnesota. The study was led by John Hardy, Ph.D., a researcher at the Institute of Neurology at University College London and a former professor at Mayo Clinic in Florida. The researchers used new sequencing techniques to home in on the TREM2 gene. Additional TREM2 sequencing was then performed, in part, by scientist Dr. Aleksandra Wojtas in the Mayo Clinic in Florida laboratory of Rosa Rademaker, Ph.D. These studies led to identification of a set of rare variants in TREM2 that occurred more often in 1,092 Alzheimer's disease patients than in a control group of 1,107 healthy people. The most common variant, R47H, was then evaluated in follow-up studies of a large number of Alzheimer's disease patients and controls. Minerva Carrasquillo, Ph.D., a scientist in the Mayo Clinic in Florida laboratory of Steven Younkin, M.D., Ph.D., spearheaded the direct genotyping and analysis of R47H in DNA samples from 1,994 Alzheimer's disease patients and 4,062 "control" participants — individuals verified not to have Alzheimer's. The patients and control participants were evaluated by Mayo Clinic physicians, led by co-authorsDennis Dickson, M.D., Neill Graff-Radford, M.D., and Ronald Petersen, M.D., Ph.D.

November 17th

Study Offers Clues to Cause of Brain Tumors in Children

Insights from a genetic condition that causes brain cancer are helping scientists better understand the most common type of brain tumor in children. In new research, scientists at Washington University School of Medicine in St. Louis have identified a cell growth pathway that is unusually active in pediatric brain tumors known as gliomas. They previously identified the same growth pathway as a critical contributor to brain tumor formation and growth in neurofibromatosis-1 (NF1), an inherited cancer predisposition syndrome. "This suggests that the tools we've been developing to diagnose and treat NF1 may also be helpful for sporadic brain tumors," says senior author David H. Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor of Neurology. The findings were published online on November 14, 2012 in Genes & Development. NF1 is among the most common tumor predisposition syndromes, but it accounts for only about 15 percent of pediatric low-grade gliomas known as pilocytic astrocytomas. The majority of these brain tumors occur sporadically in people without NF1. Earlier research showed that most sporadic pilocytic astrocytomas possess an abnormal form of a signaling protein known as BRAF. In tumor cells, a piece of another protein is erroneously fused to the business end of BRAF. Scientists suspected that the odd protein fusion spurred cells to grow and divide more often, leading to tumors. However, when they gave mice the same aberrant form of BRAF, they observed a variety of results. Sometimes gliomas formed, but in other cases, there was no discernible effect or a brief period of increased growth and cell division. In other studies, the cells grew old and died prematurely. Dr.

Probing Mystery of the Venus Fly Trap's Botanical Bite

Plants lack muscles, yet in only a tenth of a second, the meat-eating Venus fly trap hydrodynamically snaps its leaves shut to trap an insect meal. This astonishingly rapid display of botanical movement has long fascinated biologists. Commercially, understanding the mechanism of the Venus fly trap's leaf snapping may one day help improve products such as release-on-command coatings and adhesives, electronic circuits, optical lenses, and drug delivery. Now a team of French physicists from the National Center for Scientific Research (CNRS) and Aix-Marseille University in Marseille, France, is working to understand this movement. They will present their findings at the 65th meeting of the American Physical Society's (APS) Division of Fluid Dynamics (DFD), November 18 – 20, 2012, in San Diego, California. The work extends findings by Dr. Yoël Forterre and researchers from Harvard University who discovered several years ago that the curvature of the Venus fly-trap's leaf changes while closing due to a snap-buckling instability in the leaf structure related to the shell-like geometry of the leaves. Mathieu Colombani, a Ph.D. student in Dr. Forterre's laboratory is now conducting experiments to elucidate the physical mechanisms behind this movement. "The extremely high pressure inside the Venus fly trap cells prompted us to suspect that changes with a cell's pressure regime could be a key component driving this rapid leaf movement," he notes. The Colombai team uses a microfluidic pressure probe to target and measure individual cells. This is a tricky experiment because it requires the living plant to be immobilized with dental silicone paste while the probe is inserted using a micromanipulator guided by binoculars. They take pressure measurements before and after leaf closure.

New Discovery Regarding Chromatin Remodeling Complexes

A new discovery from researchers at the Huntsman Cancer Institute (HCI) at the University of Utah concerning a fundamental understanding about how DNA works will produce a "180-degree change in focus" for researchers who study how gene packaging regulates gene activity, including genes that cause cancer and other diseases. The discovery, by Bradley R. Cairns, Ph.D., Senior Director of Basic Science at HCI and a professor in the Department of Oncological Sciences, is reported in the November 11, 2012 online issue of the journal Nature. Dr. Cairns's research focuses on chromatin remodeling complexes (CRCs), which are cellular protein complexes that behave like motors, expanding or compacting different portions of DNA to either express or silence genes, respectively. Before, scientists thought that the motor within CRCs waits at rest until it receives instructions. Dr. Cairns and co-author Dr. Cedric R. Clapier show that the motor within a key CRC responsible for gene packaging and assembly is intrinsically turned on, and instead requires specific instructions to turn it off. "Many articles in the research literature show that CRCs are mutated in cancer cells. They are intimately involved in regulating gene expression—responsible for correctly packaging genes that control growth proliferation and for unpackaging tumor suppressors," said Dr. Cairns. "This research reveals principles by which CRC mutations could cause cancer." Chromosomes are made of long DNA strands compressed around nodes of protein called nucleosomes; when DNA is compressed, the genes in that area are turned off. Some CRCs, called disassembly CRCs, act as motors that unwind sections of DNA chains, making genes active for a given cell process. Another type, called assembly CRCs, rewinds the DNA chain, recompressing it when the process is complete.

November 16th

Class of Small RNA Molecules Protects Germ Cells from Damage

Passing one's genes on to the next generation is a mark of evolutionary success. So it makes sense that the body would work to ensure that the genes the next generation inherits are exact replicas of the originals. New research by biologists at the University of Pennsylvania School of Veterinary Medicine (Penn Vet) has now identified one way the body does exactly that. This protective role is fulfilled in part by a class of small RNA molecules called pachytene piwi-interacting RNAs, or piRNAs. Without them, germ cell development in males comes to a halt. Because these piRNAs play such an important role in allowing sperm to develop normally, the research indicates that defects in these molecules or the molecules with which they interact may be responsible for some cases of male infertility. Dr. Jeremy Wang, an associate professor of developmental biology and director of the Center for Animal Transgenesis and Germ Cell Research at Penn Vet, and Dr. Ke Zheng, a postdoctoral researcher in Dr. Wang's lab, authored the study, which appeared November 15, 2012 in PLOS Genetics. Scientists know of 8 million different piRNAs in existence; they are the most abundant type of small non-coding RNA. The molecule piRNA gets its name because it forms complexes with piwi proteins. Earlier work had indicated that these piwi-piRNA complexes suppress the activity of transposable elements or "jumping genes," which are stretches of DNA that can change position and cause potentially damaging genetic mutations. These sequences are also known as transposons. "There are about 50 human diseases caused by transposable elements, so it's important for the body to have a way to try to repress them," Dr. Wang said.

Gene Variant Distinguishes Early Birds from Night Owls; Helps Predict Time of Day One Is Likely to Die

Many of the body's processes follow a natural daily rhythm or so-called circadian clock. There are certain times of the day when a person is most alert, when blood pressure is highest, and when the heart is most efficient. Several rare gene mutations have been found that can adjust this clock in humans, responsible for entire families in which people wake up at 3 a.m. or 4 a.m. and cannot stay up much after 8 at night. Now new research has, for the first time, identified a common gene variant that affects virtually the entire population, and which is responsible for up to an hour a day of your tendency to be an early riser or night owl. Furthermore, this new discovery not only demonstrates this common polymorphism influences the rhythms of people's day-to-day lives -- it also finds this genetic variant helps determine the time of day a person is most likely to die. The surprising findings, which appear in the September 2012 issue of the Annals of Neurology, could help with scheduling shift work and planning medical treatments, as well as in monitoring the conditions of vulnerable patients. "The internal 'biological clock' regulates many aspects of human biology and behavior, such as preferred sleep times, times of peak cognitive performance, and the timing of many physiological processes. It also influences the timing of acute medical events like stroke and heart attack," says first author Andrew Lim, M.D., who conducted the work as a postdoctoral fellow in the Department of Neurology at Beth Israel Deaconess Medical Center (BIDMC) in Boston. "Previous work in twins and families had suggested that the lateness or earliness of one's clock may be inherited and animal experiments had suggested that the lateness or earliness of the biological clock may be influenced by specific genes," adds Dr.

Vitamin D3 Deficiency Linked to Type 1 Diabetes

A study led by researchers from the University of California, San Diego School of Medicine has found a correlation between vitamin D3 serum levels and subsequent incidence of type 1 diabetes. The six-year study of blood levels of nearly 2,000 individuals suggests a preventive role for vitamin D3 in this disease. The research appears in the December 2012 issue of Diabetologia, a publication of the European Association for the Study of Diabetes (EASD). "Previous studies proposed the existence of an association between vitamin D deficiency and risk of type 1 diabetes, but this is the first time that the theory has been tested in a way that provides the dose-response relationship," said Cedric Garland, DrPH, FACE, professor in UCSD's Department of Family and Preventive Medicine. This study used samples from millions of blood serum specimens frozen by the Department of Defense Serum Registry for disease surveillance. The researchers thawed and analyzed 1,000 samples of serum from healthy people who later developed type 1 diabetes and 1,000 healthy controls whose blood was drawn on or near the same date but who did not develop type 1 diabetes. By comparing the serum concentrations of the predominant circulating form of vitamin D – 25-hydroxyvitamin D (25(OH)D) – investigators were able to determine the optimal serum level needed to lower an individual's risk of developing type 1 diabetes. Based mainly on results of this study, Dr. Garland estimates that the level of 25(OH)D needed to prevent half the cases of type 1 diabetes is 50 ng/ml. A consensus of all available data indicates no known risk associated with this dosage. "While there are a few conditions that influence vitamin D metabolism, for most people, 4000 IU per day of vitamin D3 will be needed to achieve the effective levels," Dr. Garland suggested.

Pig Genome Sequenced

An international scientific collaboration that includes two Kansas State University researchers is bringing home the bacon when it comes to potential animal and human health advancements, thanks to successfully mapping the genome of the domestic pig. The sequenced genome gives researchers a genetic blueprint of the pig. It includes a complete list of DNA and genes that give pigs their traits like height and color. Once all of the genetic information is understood, scientists anticipate improvements to the animal's health as well as human health, as pigs and humans share similar physiologies. "With the sequenced genome we have a better blueprint than we had before about the pig's genetics and how those genetic mechanisms work together to create (characteristics), such as the unique merits in disease resistance," said Dr. Yongming Sang, research assistant professor of anatomy and physiology at Kansas State University. For three years, Dr. Sang worked on the genome sequencing project with Dr. Frank Blecha, associate dean for the College of Veterinary Medicine and university distinguished professor of anatomy and physiology. A report of the international study appears as the cover story of the November 15 issue of the journal Nature. The sequencing effort was led by the Swine Genome Sequencing Consortium. Researchers with the consortium inviting Drs. Sang and Blecha to work on the project because of their expertise and published studies on the antimicrobial peptides and interferons that pigs use to genetically defend themselves against disease. Drs. Sang and Blecha focused on these two families of immune genes, looking for gene duplications and gene-family expansions throughout the pig's 21,640 protein-coding genes, in an effort to help scientists with future pig-related research. Dr.

November 13th

Origins Matter for Brain Tumors

Cancers arise when a normal cell acquires a mutation in a gene that regulates cellular growth or survival. But the particular cell this mutation happens in—the cell of origin—can have an enormous impact on the behavior of the tumor, and on the strategies used to treat it. Robert Wechsler-Reya, Ph.D., professor and director of the Tumor Development Program in Sanford-Burnham’s NCI-designated Cancer Center, and his team study medulloblastoma, the most common malignant brain cancer in children. A few years ago, they made an important discovery: medulloblastoma can originate from one of two cell types: 1) stem cells, which can make all the different cell types in the brain or 2) neuronal progenitor cells, which can only make neurons. Stem cells and progenitor cells are regulated by different growth factors. So, Dr. Wechsler-Reya thought, maybe the tumors arising from these cells respond differently to different therapies. In a study published October 8, 2012 in the journal Oncogene, he and his team show that this is indeed the case. They looked at one growth factor in particular—basic fibroblast growth factor (bFGF)—and found that while it induces stem cell growth, it also inhibits neuronal progenitor cell growth. What’s more, the researchers discovered that bFGF also blocks the growth of tumors that originate from progenitors. When they treated a mouse model of medulloblastoma with bFGF, it dramatically inhibited tumor growth. Although bFGF itself can’t be used as a drug (it would cause too many off-target effects), this study suggests that molecules like it might be used to treat medulloblastoma—but only for tumors that have the appropriate origins. “Medulloblastomas are not all alike, and the same is true for cancers of the breast, prostate, and other tissues.