'Gatekeepers' Of Breast Cancer Transition To Invasive Disease Identified By Scientists

Scientists have made a significant discovery that clarifies a previously poorly understood key event in the progression of breast cancer. The research, published by Cell Press in the May issue of the journal Cancer Cell, highlights the importance of the microenvironment in regulating breast tumor progression and suggests that it may be highly beneficial to consider therapies that do not focus solely on the tumor cells but are also targeted to the surrounding tissues.



Progression of breast cancer begins with abnormal epithelial proliferation that progresses into localized carcinoma, called ductal carcinoma in situ (DCIS); invasive carcinoma; and eventually, metastatic disease. DCIS is believed to be a precursor to invasive ductal carcinoma, but comprehensive molecular profiling studies comparing DCIS and invasive ductal carcinomas have not yielded tumor-stage-specific genetic signatures. "These studies have focused mainly on the tumor epithelial cells and have not explored the role of the microenvironment in tumor expression," says lead study author Dr. Kornelia Polyak from the Dana-Farber Cancer Institute in Boston.



Dr. Polyak and colleagues explored the involvement of the microenvironment in tumor progression by examining myoepithelial cells, which are known to play a critical role in mammary gland development and to have negative effects on tumor cell growth and invasion. To study the interactions between breast cancer cells and myoepithelial cells, the researchers used a human model of breast tumor progression called MCFDCIS, which forms DCIS-like lesions that spontaneously progress to invasive tumors, a pathology that closely resembles human disease.



Using this model, the researchers observed that normal myoepithelial cells suppress tumor growth and invasion in the absence of detectable genetic changes in the tumor epithelial cells. They went on to identify an intricate network involving TGFb, Hedgehog, cell adhesion, and p63 that appears to play a critical role in myoepithelial cell differentiation. Perturbation of key mediators of these signaling pathways led to a loss of myoepithelial cells and a progression to invasion.



"Here, we show that a key event of tumor progression is the disappearance of the myoepithelial cell layer due to defective myoepithelial cell differentiation regulated by intrinsic and microenvironment signals. Thus, myoepithelial cells can be considered gatekeepers of the in situ to invasive carcinoma transition; understanding the pathways that regulate their differentiation may open new venues for cancer therapy and prevention," offers Dr. Polyak.







The researchers include Min Hu and Jun Yao of Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA; Danielle K. Carroll of Harvard Medical School in Boston, MA; Stanislawa Weremowicz of Brigham and Women's Hospital and Harvard Medical School in Boston, MA; Haiyan Chen of Dana-Farber Cancer Institute and Harvard School of Public Health in Boston, MA; Daniel Carrasco of Dana-Farber Cancer Institute in Boston, MA; Andrea Richardson of Brigham and Women's Hospital and Harvard Medical School in Boston, MA; Shelia Violette of Biogen-Idec in Cambridge, MA; Tatiana Nikolskaya and Yuri Nikolsky of GeneGo, Inc. in St. Joseph, MI; Erica L. Bauerlein and William C. Hahn of Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA; Rebecca S. Gelman of Dana-Farber Cancer Institute and Harvard School of Public Health in Boston, MA; Craig Allred of Washington University School of Medicine in St. Louis, MO; Mina J. Bissell of Lawrence Berkeley National Laboratory in Berkeley, CA; Stuart Schnitt of Harvard Medical School and Beth-Israel Deaconess Medical Center in Boston, MA; and Kornelia Polyak of Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA.



This work was supported in part by NIH, DOD, and ACS grants, a Susan G. Komen Foundation fellowship, Biogen-Idec., and Novartis Pharmaceuticals, Inc.



Hu et al.: "Regulation of In Situ to Invasive Breast Carcinoma Transition." Publishing in Cancer Cell 13, 394-406, May 2008. DOI 10.1016/j.ccr.2008.03.007 cancercell/



Source: Cathleen Genova


Cell Press

Muscle May Be Protected From Atrophy By A Natural Hormone

Researchers have found a potential new treatment for the common problem of muscle atrophy. Results of the animal study were presented at The Endocrine Society's 91st Annual Meeting in Washington, D.C.



Muscular atrophy is a debilitating process that results in an extensive loss of muscle mass and function, which greatly worsens quality of life. It occurs in diseases such as cancer, diabetes, AIDS and heart failure, negatively affecting the patients' prognosis. Also, muscular atrophy can occur with aging, inadequate food intake such as in anorexia nervosa, or disuse (in those who are bedridden or who must keep a limb immobile) or as a side effect of glucocorticoid steroid therapy. Nerve injury also triggers severe muscular atrophy.



Currently, there are few options to treat the problem. Some of the treatments, such as anabolic steroids (testosterone) and insulin-like growth factor 1 (IFG-1), raise concerns about safety and effectiveness, said study co-author Andrea Graziani, PhD. He is a molecular biologist with the Department of Clinical and Experimental Medicine and the Biotechnology Center for Applied Medical Research, University of Piemonte Orientale, Novara, Italy.



"Because of the wide impact of muscular atrophy on public health, it is of pivotal importance to find new and better drug strategies to treat it," Graziani said.



Graziani and his co-workers are studying des-acyl ghrelin, a form of ghrelin, the appetite-stimulating hormone found in the body. Until recently, researchers thought that des-acyl ghrelin was inactive because it does not share the main activities of ghrelin-stimulating appetite, fat and the release of growth hormone.



However, Graziani's group recently found that des-acyl ghrelin shares some biological activities with ghrelin, such as stimulating differentiation of other cells, including - important to this study - cells that are precursors to skeletal muscle cells.



In this new study, the researchers discovered that des-acyl ghrelin has a direct anti-atrophic activity on the skeletal muscle of mice with muscular atrophy caused by either denervation (nerve injury) or fasting. Mice that were genetically altered to have increased levels of des-acyl ghrelin had less skeletal muscle loss than the untreated control mice. This held true for both causes of muscular atrophy.



The mechanism by which des-acyl ghrelin protects muscle against atrophy is not yet known, the authors reported. However, it is distinct from the action of anabolic steroids and IGF-1.



Notes:

The following Italian agencies supported this work: Telethon, Regione Piemonte, and Italian Ministry for University and Research. Nicoletta Filigheddu, a researcher at the University of Piemonte Orientale's Biotechnology Center, will present the study's findings.



Source:
Aaron Lohr


The Endocrine Society

Using A Pest's Chemical Signals To Control It

Agricultural Research Service (ARS) scientists are tapping into the biochemistry of one of the world's most damaging insect pests to develop a biocontrol agent that may keep the pest away from gardens and farms.



Aphids spread diseases that cost gardeners and farmers hundreds of millions of dollars each year. Some of the insecticides available are not environmentally friendly, and because aphids are developing insecticide resistance, some growers are being forced to use more of the chemicals.



Ronald J. Nachman, a chemist with the ARS Southern Plains Agricultural Research Center at College Station, Texas, is working with chemical signals known as neuropeptides that aphids and other organisms use to control and regulate a wide range of body functions, such as digestion, respiration, water intake and excretions. The effect triggered by the chemical signal is normally turned off when the neuropeptide is broken down by enzymes in the body. Nachman is developing neuropeptide mimics, or analogues, with slightly altered molecular structures that will not break down. His goal is to kill the pest by disrupting its digestion, water intake or some other biological function.



Nachman, along with Guy Smagghe of Ghent University in Belgium and other colleagues, mixed five candidate analogues into dietary solutions and fed each one to 20 caged pea aphid (Acyrthosiphon pisum) nymphs. The scientists found that one of the formulations killed 90 to 100 percent of the aphids within three days, at a rate and potency comparable to insecticides now on the market. The study was recently published in the journal Peptides.



Any biocontrol agent would have to be thoroughly tested before being released for commercial use. Nachman is continuing to test and evaluate the neuropeptide mimics. But he said the molecular structures of the class of neuropeptide he is studying, known as insect kinins, are so unique that such a biocontrol agent is unlikely to have any effect on humans, plants or other types of organisms.



ARS is the principal intramural scientific research agency of the U.S. Department of Agriculture (USDA). The research supports the USDA priority of promoting international food security.



Source:

Dennis O'Brien

United States Department of Agriculture-Research, Education, and Economics

The Lives Of Stroke Patients Could Be Saved By Leukemia Drug

The drug tPA is the most effective treatment currently available for stroke patients, but its safety is limited to use within the first three hours following the onset of symptoms. After that, tPA may cause dangerous bleeding in the brain. However, in a study published in Nature Medicine, investigators from the Stockholm Branch of the Ludwig Institute for Cancer Research (LICR) and the University of Michigan Medical School show that these problems might be overcome if tPA is combined with the leukemia drug, imatinib (Gleevec®). The results demonstrate that imatinib greatly reduces the risk of tPA-associated bleeding in mice, even when tPA was given as late as five hours after the stroke had begun. The LICR team, in collaboration with the Karolinska University Hospital in Stockholm, is now planning a clinical trial with imatinib in stroke patients.



According to the World Health Organization (WHO), 80 percent of the 15 million strokes that occur each year are caused by the type of blood clots in the brain that tPA can dissolve. Today, less than 3% of patients with this type of stroke receive tPA because the narrow safety window has often passed by the time a stroke patient reaches a hospital and is diagnosed. If the planned clinical trial with stroke patients in Sweden confirms the findings of the present study, there is great promise that imatinib or similar drugs could be administered to stoke patients to increase the therapeutic window of tPA.



The basis for this novel proposal is the key growth factor PDGF-CC, which has now been discovered to control the blood brain barrier (a structure that normally shields the brain from the blood). When tPA acts on PDGF-CC, the blood-brain barrier becomes porous and can start to leak. Imatinib inhibits the detrimental effect of PDGF-CC by binding to its receptor PDGFR alpha, seemingly without hindering tPA's therapeutic effect, which is to break down clots that have lodged in the brain's blood vessels.



"Ten years ago our research group identified the growth factor PDGF-CC, and we are now very excited having unraveled a mechanism in the brain involving this factor", says Professor Ulf Eriksson, who leads the LICR team. "This finding has indeed the potential to revolutionize the treatment of stroke."







This study was conducted by investigators from: Ludwig Institute for Cancer Research, Stockholm Branch, Sweden; University of Michigan Medical School, Ann Arbor, USA; Karolinska Institute, Stockholm, Sweden; University of Maryland, Baltimore, USA; and Emory University, Atlanta, USA. Funding was provided by the Ludwig Institute for Cancer Research, the National Institutes of Health, the Novo Nordisk Foundation, the Swedish Research Council, the Swedish Cancer Foundation, the LeDucq Foundation and the Inga-Britt and Arne Lundberg Foundation.



About LICR



The Ludwig Institute for Cancer Research (LICR) is the largest international non-profit institute dedicated to understanding and controlling cancer. With operations at 73 sites in 17 countries, LICR's research network quite literally spans the globe. LICR has developed an impressive portfolio of reagents, knowledge, expertise, and intellectual property, and has also assembled the personnel, facilities, and practices necessary to patent, clinically evaluate, license, and thus translate, the most promising aspects of its own laboratory research into cancer therapies.



Source: Sarah White


Ludwig Institute for Cancer Research



View drug information on Gleevec.

Cockroach-like robot leads new research effort

BERKELEY - A cockroach-like robot named RHex is the starting point for a major project to understand animals' most distinguishing trait - how they move without falling over.


The National Science Foundation (NSF) announced today (Thursday, Sept. 16) a $5 million, five-year grant to the University of California, Berkeley, that will fund an all-star team of biologists, engineers and mathematicians from universities across the country to try to understand the mechanical and neurological basis of locomotion. The grant is one of six totaling nearly $30 million through NSF's Frontiers in Integrative Biological Research (FIBR) program, which supports integrative research that addresses major questions in the biological sciences.


"The hallmark of life is movement," said Robert Full, professor of integrative biology at UC Berkeley and leader of the team. "Yet, no single systems-level model, reaching from neurons to muscles to the skeleton to the whole body, can explain the control that makes movement possible. You have so many nerves and so many muscles, how in the world do you actually move forward?"


Researchers from UC Berkeley, the University of Michigan, Princeton University, Cornell University and Montana State University will focus on RHex, a short, six-legged robot that scampers like a cockroach, as a working model of the principles they're seeking to uncover. By tweaking the robot and using it as a physical model, they hope to tease apart the complex neural and muscular networks in insects.



At the same time, they will conduct biomechanical and neurological experiments on insects and develop mathematical models to improve the robot. This multi-pronged approach will allow them to uncover the neural and muscular control and feedback loops that lead to the remarkably similar patterns of whole-body motion in animals as diverse as crabs, cockroaches, lizards, dogs and humans.



"The robot has to operate in the real world, like the animal does, so we can use it for testing hypotheses," Full said. "We know, for example, that the body's center of mass bounces along like a pogo stick, which is embodied in the robot, but we don't know how its parts - its legs, feet, actuators or muscles - sum up to give that remarkably general pattern of movement.



"Now we can ask questions like, 'What if you had a more compliant leg? What if you had two joints in that leg, what does that give you versus one joint?' We can start putting artificial muscles in. Of course, that will make a better robot, but that is not the goal of this program."



Full has studied animal locomotion for 30 years, providing important insight not only to biologists, but also to engineers who have designed robots like RHex that mimic the movements of animals. RHex was built by Full's collaborators at the University of Michigan, led by Daniel Koditschek, professor of electrical engineering and computer science. But Full has contributed to other robots too: Ariel, which walks like a crab and was designed to operate in the surf zone and right itself if upended; Mecho-Gecko, which climbs up walls; and the Stanford-built Sprawlita, which bounces five body lengths at a time thanks to six piston-driven legs.















But, he admits, a biologist and an engineer can go only so far in understanding locomotion without the help of mathematicians and specialists in dynamics who can create models that can be tested on animals and robots. Full has coined the phrase "neuromechanical systems biology" for this multidisciplinary approach, which integrates data across mathematical models, numerical simulations, robot models and biological experiments.


The team he has assembled represents the best in these areas. While Full has run cockroaches, crabs, geckos and other animals on treadmills, across gelatin and over complex terrains to understand their stability, he is eager to team up with an experimental neurophysiologist who is able to interpret insects' neural code. John Miller, a professor of cell biology and neuroscience and director of the Center for Computational Biology at Montana State University, Bozeman, hopes to be able to rewrite that code while measuring motion, forces and neuromuscular signals. They will work closely with two mathematicians - Philip Holmes, professor of mechanical and aerospace engineering at Princeton University, and John Guckenheimer, professor of mathematics and theoretical and applied mechanics at Cornell University - who will analyze animal data to produce the mathematical models. The models will, in turn, provide feedback to Koditschek's robotic cockroach, which will serve as a controlled experiment that's easier to manipulate than real animals but able to tackle real-world challenges.



"This robot, the most mobile one built and created from the fundamental principles of what we know about animals, is going to help us address the grand challenge in biology - how they move," Full said.



NSF's FIBR program encourages investigators to identify major understudied or unanswered questions in biology and to use innovative approaches to address them by integrating the scientific concepts and research tools from across disciplines, including biology, mathematics and the physical sciences, engineering, social sciences and the information sciences. Among the other projects funded by NSF this year are BeeSpace, an interactive environment for studying social behavior in honey bees; a project that will examine how species that live together, evolve together; and a project examining how climate affects genetic variation and evolution.



"FIBR is one of the premier, crosscutting programs in biology at NSF," said Mary Clutter, head of NSF's Biological Sciences directorate. "By undertaking highly innovative and broadly integrative approaches to research in biology, FIBR projects tackle grand challenges and promote the training of a new and fearless generation of scientists willing and able to bridge conventional disciplinary boundaries."


Contact: Robert Sanders

rlspa.urel.berkeley

510-643-6998

University of California - Berkeley

Ecological Consequences Of Late Quaternary Extinctions Of Megafauna

As humans spread over the globe from about 50 000 years ago, megafauna such as mammoths, giant kangaroos and many others vanished. How did this sudden loss of large herbivores affect ecosystems?



This review finds evidence that in many places vegetation types changed dramatically, becoming less open and less diverse. Many plant species that evolved in environments with megafauna may be in long-term decline, for example because they now lack effective seed dispersers.



To properly understand and conserve living vegetation, we need to consider how it was once shaped by giant animals, and if possible re-create those interactions.



Proceedings of the Royal Society B: Biological Sciences


Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of the journal is diverse and is especially strong in organismal biology.


rspb.royalsocietypublishing

BD Biosciences Announces First Winners Of Expanded Research Grant Program

BD Biosciences, a segment of BD (Becton, Dickinson and Company), announced the first seven winners of its expanded BD Biosciences Research Grant Program who will receive research reagents valued at a total of $70,000 to conduct innovative cellular analysis research.


"Even in tough economic times, life science research must go on because it's important to the health of our economy, and more importantly, the health of our society," said Robert Balderas, Vice President of Biological Sciences, BD Biosciences. "BD Biosciences expanded the grant program for that very reason and hopes the winners' research will increase our understanding of disease and lead to important biomedical breakthroughs."


An independent panel of distinguished scientists selected the winners. Each grant recipient will receive a $10,000 grant of research reagents to help carry out their research.The winners of the BD Biosciences Research Grant Program for this cycle are:


Jeffrey A. Gold, M.D., is Associate Professor of Medicine at the Oregon Health and Sciences University. Dr. Gold's research focuses on sepsis, a system-wide bacterial infection that is the tenth leading cause of death in the United States.In septic patients, eosinophils, immune system cells that fight infection, are depleted while neutrophils are weakened. Dr. Gold will explore the hypothesis that interleukin-5 can rescue immune system components that are crucial for fighting sepsis. Dr. Gold's abstract is titled, "Novel Role for IL-5 in Sepsis."


Mary Cloud B. Ammons, Ph.D., is a research scientist in the Center for Biofilm Engineering at Montana State University. Dr. Ammons studies biofilm, a specialized state in which bacteria exist as a colony instead of free-standing organisms. Dr. Ammons will study the interactions between biofilms and the innate immune system, which consists of macrophages and neutrophils. The hope is that inducing macrophages to enter an anti-inflammatory vs. a pro-inflammatory phenotype will result in new treatments for biofilm-associated illness such as chronic infections and non-healing sores. Dr. Ammons' abstract is titled, "Immunity to Bacterial Biofilm."


Peter Antinozzi, Ph.D., is Assistant Professor in the Departments of Biochemistry and Internal Medicine, Wake Forest University School of Medicine. One of the challenges to analyzing biopsy samples is conducting "high content" screens from a small amount of very valuable tissue. Dr. Antinozzi, who is studying changes occurring in kidney cells in patients in diabetic nephropathy, uses automated confocal fluorescence microscopy to image all kidney cell types with a minimum of sample preparation. His work will directly benefit scientists who analyze human cells implicated in chronic diseases, and specifically could lead to diagnostic or prognostic tests for diabetic nephropathy. Dr. Antinozzi's abstract is titled, "A Novel High-Content Assay for Renal Cell Biology."


Melanie Dart, Ph.D., is an Assistant Scientist at the University of Wisconsin, Madison. Her work centers on immune system T-cell interactions with collagen V, a protein involved in the development and progression of atherosclerotic plaque. Dr. Dart will analyze blood and plaque samples from patients who have undergone vascular surgery to determine the correlation between plaque pathology and populations of two important classes of T-cells: regulatory T-cells, which suppress the inflammatory immune response, and effector T-cells, which induce it. The ultimate goal is therapies that suppress undesirable immune responses to atherosclerotic plaque. Dr. Dart's abstract is titled, "Atherosclerosis and Collagen V."















Nilufer Esen-Bilgin, M.D., is a Research Fellow at the University of Michigan. Her research interests lie in sindbis virus, an alphavirus that causes neuronal death in mice and serves as a model for human neurologic disease. Dr. Esen-Bilqin will attempt to unravel the immune response to sindbis infection, which is believed to result in neural damage. Knowing which specific macrophages and T-cells are infiltrating the nervous systems of infected animals will shed light on the pathology of sindbis-associated nerve damage, and it is hoped, analogous human diseases. Dr. Esen-Bilqin's abstract is titled, "Infiltrating Myeloid Cells."


Celine S. Lages, Ph.D. is a Postdoctoral Research Fellow at the Cincinnati Children's Hospital Medical Center. One consequence of aging is an attenuated immune response and the subsequent emergence of immune-associated disorders. Dr. Lages will study the impact of regulatory T-cells (Treg) on this process. Treg cells are super-regulators of the immune response: too high and immune competence decreases, while too little can result in autoimmunity. Understanding the conversion of "ordinary" T-cells to Treg in aging could lead to therapies that prevent that transformation, and thereby reduce the consequences of waning immunity. Dr. Lages' abstract is titled, "Role of Peripheral Conversion in Regulatory T-Cell Accumulation in Aging."


H. Scott Rapoport, Ph.D. is a Senior Scientist at Tengion, Inc., which researches the re-growth of organs and tissues using a combination of a patient's own cells and a biocompatible material. The success of such implants, known as "constructs," can depend on the activation states of macrophages. Initial work will focus on the point at which activation is initiated, and the contribution of the construct towards activation states leading to construct acceptance and rejection. This understanding should lead to rational design of constructs that induce favorable macrophage responses.Dr. Rapoport's abstract is titled, "Macrophage Diversity."


The expanded BD Biosciences Research Grant Program will award another seven scientists a total of $70,000 worth of research reagents in May 2010 to help cover year-round research needs. Grant applications should focus on research in one of seven core areas: stem cell, multicolor flow cytometry, cell signaling, cancer, immune function, infectious diseases and neurosciences.


Additional information about the grant program, including the application process and deadlines, is available here.


About the BD Biosciences Research Grant Program


BD Biosciences' Research Grant Program aims to reward and enable important research by providing vital funding for scientists pursuing innovative experiments to advance the scientific understanding of disease. The grant submissions are judged by a distinguished research panel of non-affiliated scientists. Through its grant program, BD Biosciences supports innovation in research and development as well as help enable the next generation of scientific breakthroughs.


Source

BD

Researchers Unveil Near Complete Protein Catalog For Mitochondria

Imagine trying to figure out how your car's power train works from just a few of its myriad components: It would be nearly impossible. Scientists have long faced a similar challenge in understanding cells' tiny powerhouses called "mitochondria" from scant knowledge of their molecular parts.


Now, an international team of researchers has created the most comprehensive "parts list" to date for mitochondria, a compendium that includes nearly 1,100 proteins. By mining this critical resource, the researchers have already gained deep insights into the biological roles and evolutionary histories of several key proteins. In addition, this careful cataloging has identified a mutation in a novel protein-coding gene as the cause behind one devastating mitochondrial disease. A full description of the work appears in the July 11 print edition of the journal Cell.


"For years, a fundamental question in cell biology has gone largely unanswered what proteins function in mitochondria?" said Vamsi Mootha, an associate member at the Broad Institute of Harvard and MIT and a Harvard Medical School assistant professor at Massachusetts General Hospital, who led the study. "By creating a comprehensive list, we now have a valuable resource that has already helped enhance our understanding of mitochondrial biology and disease."


Mitochondria are linchpins of cellular life, found within the cells of all eukaryotes from yeast to humans. These miniaturized organs ("organelles") are well known for their role in providing cellular energy. They have also been implicated in a wide range of normal and disease processes, including diabetes, neurodegeneration, cancer, drug toxicity and aging.


Although mitochondria have their own genome a vestige from their days as free-living bacteria the vast majority of the critical mitochondrial proteins are derived not from their genome, but rather from the nuclear genome. However, even with the wealth of genome sequence data now available, scientists have struggled to identify which genes encode the roughly 1,200 proteins that make up a functional mitochondrion.


Researchers from the Broad Institute, Harvard Medical School, and Massachusetts General Hospital worked together to address this problem, drawing on the power of a multi-faceted approach that includes large-scale, mass spectrometry-based proteomics to measure proteins in mitochondria from a variety of tissues; computational methods to help identify those proteins that cannot be reliably detected; and microscopy to confirm within human cells the localization of presumptive mitochondrial proteins.


"The technologies and analytical methods for measuring proteins on a large scale are really transforming what we can learn about human biology," said Steve Carr, director of the Proteomics Platform at the Broad Institute and a co-author of the Cell paper. "By applying them to mitochondria isolated from fourteen different mouse tissues, we've completed one of the most comprehensive proteomic analyses of any organelle to date."















As a result of their analyses, the researchers identified a total of 1,098 mitochondrial proteins to form a compendium they have named "MitoCarta," and which is available to the entire scientific community. Notably, about one-third of this inventory has not been previously linked to the organelle.


To shed light on the functions of the newly uncovered mitochondrial proteins, the researchers compared the proteins' corresponding gene sequences across hundreds of species, from humans and fish to fungi and bacteria. "Proteins with similar roles often share similar histories, meaning they're gained or lost together during evolution," said Mootha. "We decided to use this tendency to our advantage to decipher how some mitochondrial proteins work."


By examining the organelle's proteins through this evolutionary lens, the researchers uncovered a striking pattern. A group of key mitochondrial proteins, known to be absent in yeast but otherwise present among eukaryotes, are actually missing from several other single-celled species. In organisms that have them, including humans and other mammals, these proteins contribute to a boot-shaped, multi-protein structure, which forms the gateway to a critical step in the energy-generation process. By virtue of these proteins' shared and unusual past, Mootha and his colleagues were able to identify several additional proteins that are also associated with this crucial mitochondrial structure, known as complex 1.


In addition to offering insights into mitochondrial biology, these discoveries also paved the way for a breakthrough in understanding mitochondrial disease. For decades, doctors have diagnosed patients with deficiencies in complex I function. These disorders affect about 1 in 5,000 newborns, are genetic in origin, and are lethal in the first few years of life. Yet for many cases a culprit gene cannot be found. However, thanks to MitoCarta and its corresponding evolutionary analyses, the researchers and their collaborators at the University of Melbourne and Royal Children's Hospital in Australia identified a mutation in a novel gene, called C8orf38, as one cause of complex I disease.


"Our finding underscores the power of this protein catalogue to open new vistas on disease," said Mootha. "It promises to shed light not only on rare metabolic diseases, but common diseases as well."


This work was supported by a grant from the National Institute of General Medical Sciences, one of the National Institutes of Health.


Paper cited:


Pagliarini DJ et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell July 11, 2008.


About the Broad Institute of MIT and Harvard


The Broad Institute of MIT and Harvard was founded in 2003 to bring the power of genomics to biomedicine. It pursues this mission by empowering creative scientists to construct new and robust tools for genomic medicine, to make them accessible to the global scientific community, and to apply them to the understanding and treatment of disease.


The Institute is a research collaboration that involves faculty, professional staff and students from throughout the MIT and Harvard academic and medical communities. It is jointly governed by the two universities.


Organized around Scientific Programs and Scientific Platforms, the unique structure of the Broad Institute enables scientists to collaborate on transformative projects across many scientific and medical disciplines.


For further information about the Broad Institute, go to broad.mit.


Media Backgrounder: A Primer on Mitochondria


1. What are mitochondria and where are they found?


Mitochondria are bean-shaped compartments within cells that supply energy. These compartments, a type of membrane-bound organelle, are found in eukaryotes organisms whose cells have nuclei, the home of the genome. Multicellular organisms (humans, mice, fish, etc.) as well as some unicellular ones, like yeast, are counted as eukaryotes. Bacteria, though, are not: They are considered prokaryotes for their lack of organelles, including mitochondria and nuclei.


Intriguingly, mitochondria vary widely across organisms and even within an organism. Drastic differences can exist in the number of mitochondria per cell, their size and morphology, and even their biochemical capabilities. For example, fatty acids readily broken down by mitochondria in muscle, but not brain tissue. Because of a lack of molecular knowledge about mitochondria and their resident proteins, the basis for such differences is largely unclear.


2. What do mitochondria do?


Although mitochondria are perhaps best known for their roles in energy metabolism, they also participate in a plethora of other key biological processes. These include critical functions such as programmed cell death (or "apoptosis"), a normal mechanism through which old or damaged cells can be eliminated.


Defects in mitochondria are associated with more than 50 human diseases, ranging from in-born errors of metabolism in infants to neurodegeneration in adults. Moreover, several common diseases, such as cancer and type 2 diabetes, have been associated with mitochondrial dysfunction. Prescription drugs can also disrupt mitochondria. Such drug-induced toxicity is a reason why some drugs are pulled from the market and why some potential drugs fail the clinical trial process.


3. Where do mitochondria come from?


Mitochondria, it turns out, have their own tiny genome. And in humans, this mitochondrial DNA is inherited solely from the mother. Such maternal inheritance arises because mitochondria from sperm are lost following fertilization, while those contributed by the egg persist. Because it is maternally inherited, mitochondrial DNA can provide clues about human history, including the most recent common matrilineal ancestor of living humans (so-called "Mitochondrial Eve".)


But there are, in fact, paternal contributions to mitochondria. The parts of the mitochondria that are derived from nuclear genes actually come from both parents (see below). This follows a core principle of human genetics: of the 23 pairs of chromosomes that make up your nuclear genome, roughly half come from Mom and the other half from Dad.


Evolutionarily speaking, mitochondria have a very interesting history. They are descendants of an ancient bacterium a relative of the modern bacterial species, Rickettsia prowazekii that some 2 billion years ago was enveloped by another cell. That moment marked the beginning of a long and mutually beneficial relationship with eukaryotic cells, known as endosymbiosis. As a result of such "co-habitation", eukaryotic cells and mitochondria have evolved and adapted to life together, such that now, neither can survive alone.


4. Where do the proteins in mitochondria come from?


Because of the organelle's unusual past, the molecular pieces that make up mitochondria have undergone some shuffling of their own. Mitochondria carry a small circular genome, a vestige of their days as free-living bacteria that has been winnowed during evolution to just a few protein-coding genes.


The human mitochondrial genome was decoded in 1981, a full 20 years before the human genome itself was decoded. The organelle's genome consists of roughly 16,000 chemical units called base pairs, much smaller than the nuclear genome's 3 billion base pairs. The mitochondrial genome includes just 37 genes: 13 genes that encode proteins and 24 additional non-protein coding genes.


The rest of the genes required for a functioning mitochondrion, roughly 1,200 to 1,500 in total, now reside in the nucleus. Identifying these genes from DNA sequence data alone has proven immensely difficult, which is why other large-scale approaches namely proteomics and computational methods are required to pinpoint them.


Broad Institute

7 Cambridge Center

Cambridge, MA 02142

United States

broad.mit

Using Lyme Disease As A Model, MU Researchers Find Inflammatory Disease Treatments Will Improve Through The Use Of Lipidomics

According to the National Center for Chronic Disease Prevention and Health Promotion, 46 million Americans have arthritis. Many of these people take over-the-counter anti-inflammatory medications that block production of certain molecules, known as bioactive lipids, to reduce pain and swelling. Yet, the role of these lipids is not yet understood completely, and medications may have adverse side effects. Recently, University of Missouri researchers completed the first comprehensive analysis of bioactive lipids in an inflammatory response triggered by the Lyme disease agent, Borrelia burgdorferi. This analysis could shed light on the role bioactive lipids play in inflammatory diseases.



"Many diseases, such as arthritis, cardiovascular disease and diabetes are associated with chronic inflammation," said Charles Brown, associate professor of veterinary pathobiology in the MU College of Veterinary Medicine. "The first step in finding an effective treatment is to understand the basics of an inflammatory response, including the role of bioactive lipids. Understanding how bioactive lipids regulate the disease processes will lead to the development of drugs that have more specific targets and less adverse side effects."



In the study, researchers investigated the role of certain bioactive lipids in mice infected with Borrelia burgdorferi, the bacteria responsible for Lyme disease. Eicosanoids, which are bioactive lipids that play an important role in inflammatory disease, were extracted from mice that displayed symptoms of Lyme arthritis and from mice who showed no symptoms. The researchers found differences in the amounts of specific eicosanoids in the samples, which correlated with the severity of arthritis in the mice.



"The process of inflammation is not a passive event, but instead is a coordinated, orderly process actively signaled by specific protein and lipid molecules," Brown said. "Previous studies investigating eicosanoids have focused on singular pathways or phases of the inflammatory response. These studies provided an incomplete picture and gave the impression that some bioactive lipids function in isolation. In our study, we were able to measure virtually all of the known eicosanoids at the same time and examine a more complete picture of the inflammatory response."



The findings from this study also could translate into a diagnostic tool for assessing individual patients, assist with the development of more disease-specific therapies, and facilitate the progress of individualized medicine, resulting in more effective treatments for inflammatory diseases with fewer side effects.



Lyme arthritis occurs in 60 to 80 percent of individuals not treated with antibiotics at the time of their infection, and patients are typically given anti-inflammatory drugs to treat their pain and swelling. Arthritis in mice caused by Lyme disease is a good model for how bioactive lipids regulate the process of inflammation, because researchers can observe the process from start to finish, Brown said.



The study, "Lipidomic Analysis of Dynamic Eicosaniod Responses During the Induction and Resolution of Lyme Arthritis," was published in the June issue of The Journal of Biological Chemistry. It was co-authored by Brown; Victoria Blaho, post doctoral researcher in the MU College of Veterinary Medicine; Matthew Buczynski, researcher at the University of California; and Edward Dennis, researcher at the University of California.



Source:
Kelsey Jackson


University of Missouri-Columbia

VIB And UZ-KU Leuven Join Forces And Bring State-of-the-art Technology To Flanders

Genome research can now be done 100 times faster



Belgium-Flemish biotechnologists have a world-wide reputation for deciphering genetic code. In order to further strengthen this leading position, two Flemish research institutes are joining forces and bringing new technology to Flanders which will record DNA 100 times faster than current methods. This is an essential asset as these DNA analyses hold the key to the decipherment and treatment of genetic disorders.



Why decipher DNA?



The full DNA of an organism -- the genome -- determines what that organism looks like and how it functions. The better we understand this, the more we can learn about the intricacies of living beings. We know the broad outline of human DNA, and scientists are now determining the DNA differences between people. These differences characterise the diversity of people but they also hold the key to a higher risk for genetic disorders such as dementia, psychosis, diseases of the heart and blood vessels, and cancer. If we know and understand the differences, we can also use them as the foundation for new treatments.



However, to record these differences efficiently, it is essential that everything moves much faster than the current technology allows. This has now become possible. So-called 'new generation' sequence technology has recently been developed, but it is still very expensive.



Nevertheless, VIB and UZ.-K.U. Leuven have joined forces to give Flemish scientists access to this state-of-the-art technology. Via a co-ordinated investment program, they are bringing Roche's DNA sequence technology platform, the so-called 454 sequencing, to Flanders.



What is 454 sequencing?



This technique provides an ingenious manner to super-efficiently decipher DNA code. DNA fragments are isolated in drops of water, which function as micro-reactors. Using these pieces of DNA, 10 million identical copies are made and they are simultaneously (but individually) sequenced. This is all done on a tablet the size of a credit card which contains 1.6 million little holes in which sequence reactions are generated. Seven hours later, the DNA sequences are produced by the computer, thereby rendering a wealth of data. This technology has the advantage of producing large parts of sequences from the genomes that are to be recorded, which benefits not only the speed but also the accuracy of the information. In short, the larger the pieces of the puzzle, the quicker and more precise the image of the entire picture.



Determining sequences can now be done 100 times faster than the technologies which are currently being used. With the next version of the new technology, which should be available within a year, one experiment will yield yet another 10 times more sequence, so 1000 times more than now. Therefore, with the new technology, Flemish scientists will in one day be able to gather DNA data that would today take 3 years to compile. This is truly revolutionary!
















Applications for VIB and UZ-K.U. Leuven



In order to make optimal use of these substantial investments, VIB and UZ-K.U.Leuven are mutually coordinating activities on both units. Both parties will exchange expertise and will make capacity available to one another. In addition, VIB and UZ-K.U.Leuven will be able to grant Flemish researchers from other centers access to this revolutionary technology via this platform.



The 454 sequencer will be embedded in the Genetic Service Facility of the VIB Department of Molecular Genetics, University of Antwerp under the direction of Christine Van Broeckhoven . New technology will be developed under the supervision of Jurgen Del-Favero, supporting basic research such as sequencing new, full genomes of interesting organisms (e.g. pathogenic organisms) and tracing DNA differences that cause illnesses. On top of that, there will be a large investment in translational research focusing on the development of more efficient and cheaper genetic diagnostic tests. The University of Antwerp guarantees a structural contribution towards the cost of this new investment.



Quote from VIB: "This technology will allow us to more quickly identify the molecular mechanisms of illness."



With this investment, UZ-K.U.Leuven wishes to stimulate translational research which will, through interaction between researchers and clinicians, generate genuine innovations in the field of patient care. A powerful DNA diagnostic platform to find mutations in genes which cause, among other things, breast and bowel cancer, or are involved in illnesses such as heart, vascular illnesses and diabetes, can contribute to significant diagnostic and therapeutic possibilities.



Quote from UZ-K.U.Leuven: "This technology brings fundamental research closer to patient applications."






Source: Ann Van Gysel


VIB, Flanders Institute for Biotechnology

A Deep Look Into Population Variation In Gene Activity Provides Key Insight Into Cell Functions And Disease Susceptibility

Our DNA contains the information needed to produce different proteins that are the building blocks and key components of cells. Instructions to synthesize such proteins are incorporated into DNA sequences defined as genes. This precious genetic material, however, never leaves the cell's stronghold nucleus. Instead, copies called RNA messengers are made and sent out to the tiny cell's protein factories located outside of the nucleus. Mutations in genes lead to a variation in the abundance or structure of these RNA messengers. This in turn is associated with changes in the protein content of cells, thereby influencing the way certain cellular processes are executed. Such DNA variations thus may contribute to differences in characteristics between individuals and may also cause or predispose to various diseases.


A new and detailed reality emerges through corrected vision


In order to elucidate the genetic nature of this variability, a collaboration of researchers from Switzerland, Spain and the UK, under the leadership of the Faculty of medicine of the UNIGE, have used novel technology to study RNA messengers. This cutting edge procedure, called "second generation sequencing", allows an unprecedented level of resolution to determine the abundance and structure of RNA messengers.


Previous studies merely informed us about rough individual differences in the quantity of RNA from each gene in the cell. Moreover, this was only the tip of the iceberg in terms of defining the exact molecular consequences. In this new research project, conducted using blood cells of 60 individuals of European descent, the scientists have obtained a much higher resolution of such processes that allow them to describe in detail the molecular differences in RNA among individuals. "For the first time we are able to "read" the sequence of almost all the RNA molecules in the cell and compare them among individuals" says Dr. Stephen Montgomery from the UNIGE.


The ability to read the RNA sequence in so many individuals is of unprecedented scale and brings the understanding of genetic variation to a new level. "The genome sequencing provided us with information to understand basic processes within the cell but the new mRNA study allows us to reach a new level on the understanding of variability between individuals" says Roderic GuigГі, coordinator of the Bioinformatics and Genomics Programme at the CRG.


Professor Emmanouil Dermitzakis from the Genetics Department of the Faculty of medicine of the UNIGE and the Frontiers in Genetics program states "Obviously, such an increase in resolution provides us with a major advance in understanding of cellular processes and the fine detail of differences between humans".


Sharper insight will pave the way to tailor made treatments


The results of this study, which has received financial support from the Wellcome Trust, the Louis-Jeantet Foundation and the Spanish Ministry of Science and Consolider program, have wider implications for human health. It is well known that DNA variants affecting gene activity may be responsible for disease susceptibility, primarily to common pathologies such as diabetes, cardiovascular diseases and asthma. The understanding of how such hitherto unknown subtle differences modulate gene expression is bound to accelerate the understanding of their mechanisms at the cellular level, enabling faster and more focused development of treatments.


As reported on line in this week's edition of Nature, this study provides a framework towards the full understanding of the impact of genetic variations in cellular interactions, which has very important implications for the understanding of human diseases.


The Ministry of Science and Innovation, the Ingenio Consolider 2010 Programme, the Wellcome Trust, the Louis-Jeantet Foundation and Swiss NSF Frontiers in Genetics have funded the project.


Source: Centre for Genomic Regulation

Nitrous Oxide: Definitely No Laughing Matter

Farmers, food suppliers, policy-makers, business leaders and environmentalists are joining forces to confront the threat of the 'forgotten greenhouse gas' by taking part in an influential new forum at the University of East Anglia (UEA).



Launched on February 22, the Nitrous Oxide Focus Group will engage with many influential organisations including the National Farmers Union, Marks & Spencer, British Sugar, Defra, the Country Land and Business Association and Unilever.



The group will present and explore cutting edge research into the sources and sinks of nitrous oxide in the environment and discuss the prospects of mitigating the release of this destructive gas through re-shaping current policies and practice.



"People are becoming increasingly concerned about the immense problems associated with the unregulated release of this potent greenhouse gas," said Prof David Richardson, Dean of the Faculty of Science at UEA and co-ordinator of the Nitrous Oxide Focus Group.



"It is very encouraging that so many key figures from agriculture, industry and government are interested in mitigating nitrous oxide emissions by learning more about key research questions that are currently being addressed with government funding by groups within UEA, along with collaborating research groups across the UK and Europe."



Better known as 'laughing gas', nitrous oxide (N2O) accounts for 9 per cent of all greenhouse gases, yet is 300 times more potent than carbon dioxide (CO2). As a result its longevity in the atmosphere provides a potentially more damaging legacy than CO2.



Agriculture accounts for around 70 per cent of N2O emissions. The sources are mainly from soil micro-organisms that make N2O from nitrogen-rich fertilisers added to soils to maximise crop yields. Other significant biological sources of N2O come from the wastewater treatment industries where the greenhouse gas is again produced from micro-organisms.



The launch of the new consortium is underpinned by more than five years of interdisciplinary research at UEA and comes as significant new research on an N2O-generating enzyme from a widespread soil bacterium is published.







Published in the Journal of Biological Chemistry (February 15 2008), the research was done in collaboration with the University of Stockholm and largely carried out by UEA graduate Faye Thorndycroft under the guidance of Prof Richardson and Dr Nick Watmough.



For more information on the Nitrous Oxide Focus Group, please visit nitrousoxide/.



Source: Simon Dunford


University of East Anglia

Columbia University takes leading role in second phase of NIH protein structure initiative

Researchers at Columbia University are taking a major role in the second phase of the National Institutes of Health's Protein Structure Initiative, leading or participating in three of the 10 new research centers announced Friday by the National Institute of General Medical Sciences (NIGMS).


The Protein Structure Initiative (PSI) is a national effort to determine the three-dimensional shapes of a wide range of proteins. This structural information will help reveal the roles that proteins play in health and disease and will help point the way to designing new medicines.


Selection of the centers, slated to receive about $300 million over the next five years, marks the second half of the decade-long initiative. Columbia University will receive about $25 million over five years to fund its research contributions.


"The overall idea of PSI is a bit like the Human Genome Project in that the information gained from these large-scale efforts will underpin a more efficient approach to medical research in the future," said Wayne Hendrickson, Ph.D., University Professor of Biochemistry and Molecular Biophysics at Columbia University Medical Center (CUMC) and leader of one of the new centers. "Drug discovery has been lagging in recent years, and many of us believe that the development of drugs based on a protein's structure is a much more efficient way to find the drugs we'd like to have."


The Protein Structure Initiative essentially starts from where the Human Genome Project left off. "Genes are important only in that they produce proteins, which are the tiny three-dimensional machines of life," says Lawrence Shapiro, Ph.D., associate professor in the Departments of Opthalmology and Biochemistry & Molecular Biophysics at CUMC, and a principal investigator of one of the new centers. "This project will enable us to see thousands of proteins in the form in which they actually do their work."


When the PSI established its pilot centers beginning in 2000, its goal was twofold: to develop innovative approaches and tools, such as robotic instruments, that streamline and speed many steps of generating protein structures, and to incorporate those new methods into pipelines that turn DNA sequence information into protein structures.


Now, according to the NIH, the focus shifts to a production phase during which the new centers will use methods developed during the pilot period to rapidly determine thousands of protein structures found in organisms ranging from bacteria to humans. These efforts will facilitate accurate structure prediction of a much larger number of proteins through computer modeling.


""We hope that the PSI will allow us to develop a new view of the relationships between protein sequence, protein structure, and protein function that will ultimately make the three-dimensional structures and functions of most proteins predictable from the protein sequence" said Barry Honig, Ph.D., professor of biochemistry and molecular biophysics at CUMC and the bioinformatics leader of the Northeast Structural Genomics Research Consortium.















"We are proud to be contributing to this important effort that is harnessing the brightest minds across a spectrum of scientific disciplines," said David Hirsh, Ph.D., executive vice president for research at Columbia University. "Through this collaborative research we will gain greater insight into how proteins function and their evolutionary interrelationships, ultimately leading to the identification of new targets for drug design."


Columbia researchers will play major roles in the following centers:


-- The New York Consortium on Membrane Protein Structure, led by Wayne Hendrickson, University Professor of Biochemistry and Molecular Biophysics at Columbia University Medical Center. Other Columbia researchers include: Drs. Burkhard Rost, Barry Honig, Lawrence Shapiro, Eric Gouaux, Ming Zhou, John Hunt, and Filippo Mancia.


-- The Rutgers-led Northeast Structural Genomics Consortium, led by Professor Gaetano Montelione of Rutgers University. Montelione and his consortium partners previously conducted a $36 million NIGMS pilot program that developed new tools that will now be utilized in this second phase of the project, which focuses on cancer-related proteins. Columbia contributors include bioinformaticians Burkhard Rost, Ph.D. and Dr. Honig, the consortium's director of bioinformatics; Dr. Hendrickson, the consortium's director of crystallography, and Drs. Peter Allen, Liang Tong, John Hunt, and Andrew Laine from Columbia University.


-- The New York Structural Genomics Research Consortium (led by Structural GenomiX, Inc, a company co-founded by Drs. Honig and Hendrickson). Dr. Shapiro, will help in high-throughput structure determination, focusing particularly on structures of phosphatases, a type of protein frequently important in disease.


Craig LeMoult

cel2113columbia

212-305-0820

Columbia University Medical Center

cumc.columbia

Fish Protein Link To Controlling High Blood Pressure, New Study

Medical scientists at the University of Leicester are investigating how a species of fish from the Pacific Ocean could help provide answers to tackling chronic conditions such as hereditary high blood pressure and kidney disease.


They are examining whether the Goby fish can help researchers locate genes linked to high blood pressure. This is because a protein called Urotensin II, first identified in the fish, is important for regulating blood pressure in all vertebrates- from fish to humans.


The study is being carried out in the University's Department of Cardiovascular Sciences. Researcher Dr Radoslaw Debiec said: "The protein found in the fish has remained almost unaltered during evolution".


"This indicates that the protein might be of critical importance in regulation of blood pressure and understanding the genetic background of high blood pressure.


"Uncovering the genetic causes of high blood pressure may help in its better prediction and early prevention of its complications. My research at the University of Leicester has shown how variation in the gene encoding the protein may influence risk of hypertension."


Dr Debiec will be presenting his research at the Festival of Postgraduate Research which is taking place on Thursday 25th June in the Belvoir Suite, Charles Wilson Building at the University of Leicester between 11.30am and 1pm.


He added: "Drugs affecting the protein might be a novel alternative to the available therapies in particular in those patients who have chronic kidney disease coexisting with high blood pressure.


"Analysis of large cohort of families has provided us with evidence that genetic information encrypted in the protein travels together with the risk of high blood pressure across generations. Furthermore, the same genetic variant responsible for elevated blood pressure is responsible for the development of chronic kidney disease in this group of patients.


"The present findings may have an impact on the development of new blood pressure-lowering medications."


Dr Debiec's study was supervised Dr. M. Tomaszewski (Department of Cardiovascular Sciences, Cardiology Group,) and Professor D.G. Lambert (Department of Cardiovascular Sciences; Pharmacology and Therapeutics Group).


Source: Leicester University

Discovery Of New Step In DNA Damage Response In Neurons

Researchers have identified a biochemical switch required for nerve cells to respond to DNA damage.



The finding, scheduled for advance online publication in Nature Cell Biology, illuminates a connection between proteins involved in neurodegenerative disease and in cells' response to DNA damage.



Most children with the inherited disease ataxia telangiectasia are wheelchair-bound by age 10 because of neurological problems. Patients also have weakened immune systems and more frequent leukemias, and are more sensitive to radiation.



The underlying problem comes from mutations in the ATM (ataxia telangiectasia mutated) gene, which encodes an enzyme that controls cells' response to and repair of DNA damage.



ATM can be turned on experimentally by treating cells with chemicals that damage DNA. After other proteins in the cell detected broken DNA needing repair, scientists had thought that the ATM protein could activate itself directly. Emory researchers have shown that an additional step is necessary first.



"In neurons that are not dividing anymore, we now know that another regulator is involved: Cdk5," says Zixu Mao, MD, PhD, associate professor of pharmacology and neurology at Emory University School of Medicine.



Working with postdoctoral fellows Bo Tian, PhD and Qian Yang, PhD, Mao found that the Cdk5 protein must activate ATM before ATM can do its job in neurons.



The results support the idea that Cdk5 may be a potential drug target. Cdk5 contributes to normal brain development, and aberrant Cdk5 activity is known to be involved in the death of neurons in several neurodegenerative diseases, including Alzheimer's, Parkinson's and amyotrophic lateral sclerosis.



"Cdk5 has a complex character," Mao says. "It can be bad for neurons if its activity is either too high or too low."



Mao says he and his colleagues were intrigued by reports that in these diseases, neurons that had stopped dividing appear to restart that process, copying their DNA, before dying.



"That's what really kicked us into high gear," he says.



The same process, called "mitotic catastrophe," occurs when neurons suffer DNA damage. Inhibiting either Cdk5 or ATM can reduce the number of neurons that suffer mitotic catastrophe after DNA damage, the authors found.







The National Institutes of Health and the Woodruff Health Sciences Center Fund supported the research.



Reference:



Tian, B., Yang, Q. and Mao, Z. Phosphorylation of ATM by CDk5 mediates DNA damage signaling and regulates neuronal death.



Nature Cell Biology, advance online publication.



The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include schools of medicine, nursing, and public health; the Yerkes National Primate Research Center; the Emory Winship Cancer Institute; and Emory Healthcare, the largest, most comprehensive health system in Georgia. The Woodruff Health Sciences Center has a $2.3 billion budget, 17,000 employees, 2,300 full-time and 1,900 affiliated faculty, 4,300 students and trainees, and a $4.9 billion economic impact on metro Atlanta.



Source: Holly Korschun


Emory University

Cells That Avoid Suicide May Become Cancerous

When a cell's chromosomes lose their ends, the cell usually kills itself to stem the genetic damage. But University of Utah biologists discovered how those cells can evade suicide and start down the path to cancer.



Details of how the process works someday may provide new ways to treat cancer.



The new study of fruit flies is the first to show in animals that losing just one telomere - the end of a chromosome - can lead to many abnormalities in a cell's chromosomes, which are strands of DNA that carry genes.



"The essential point is that loss of a single telomere may be a primary event that puts a cell on the road to cancer," says Kent Golic, a professor of biology at the University of Utah and senior author of the study, which will be published online this week in the December issue of the journal Genetics.



Fruit flies have four pairs of chromosomes. Humans have 23 pairs. Each chromosome has two ends, called telomeres, which often are compared with the plastic tips of shoe laces. When those tips are lost or break, the shoelace frays. Previous research has shown that aging and cancer often are associated with loss or shortening of telomeres.



Damaged Cells Usually Kill Themselves to Avoid Becoming Cancerous



To protect an organism against cancer, most cells with broken or missing telomeres undergo "apoptosis," also known as cell suicide. But Golic and Simon Titen, a postdoctoral fellow in biology, found how fruit fly cells with a missing telomere sometimes avoid suicide and instead continue to divide and develop early characteristics of cancer.



Normally when a chromosome is damaged, the cell carrying the chromosome turns on a gene named p53, which helps kill the cell. When mutated, p53 fails to carry out this vital function. That is why mutant p53 is a cancer-causing gene and is found in most human tumors.



Golic and Titen found that normal p53 and so-called "checkpoint" proteins named Chk1 and Chk2 are required for the suicide of fruit fly cells with a missing telomere.



They also found that a non-mutant cell lacking a telomere occasionally escapes suicide and divides. Then, its progeny accumulate defects, including the wrong number of chromosomes or chromosomes that have exchanged pieces with each other. Those defects are hallmarks of cancer cells.



One possible reason a cell avoids suicide even after telomere loss and other damage is that chromosomes in the cell's offspring regain telomeres.



"All cancer cells have figured out how to add new telomeres, which allows them to survive and divide indefinitely," says Titen. "By interfering with this process, it might be possible to provide a route therapeutically to treat cancer."



A telomere is made of short sequences of DNA repeated hundreds of times. Proteins bind to the DNA, forming a cap or telomere that protects the end of the chromosome.
















In humans, cells in certain tissues, such as the skin, continue to divide over a lifetime. Each time a cell divides, the telomeres become shorter until, in rare cases, the rest of the chromosome is no longer protected. It has been proposed that this can trigger cancer, but previous studies have been done only in yeast or cultured animal cells that are grown in a dish. The new Utah study shows in flies that telomere loss can cause cancer-like changes in a cell.



When Cell Suicide is Blocked, Cells Start on the Road to Cancer



Fruit flies often are used for chromosomal studies because they share 60 percent of their genes with humans, and it is unethical to cause genetic abnormalities in humans. Also, the process by which fly cells grow and divide are comparable with human cells.



To trigger telomere loss, the researchers inserted into the flies a gene from common baker's yeast. The gene makes an enzyme that breaks and rejoins DNA. When they turned on the enzyme, it led to the loss of a single telomere in each affected fruit fly cell.



The researchers then looked at what happened to the cells that lost a telomere.



"When we looked to see what happens to cells [those lacking a telomere], we found that most died - which is good - because those that didn't die accumulated abnormal chromosomes, which is characteristic of cancer cells," Golic explains.



Next, they repeated the experiment using flies in which p53, Chk1 or Chk2 were mutated - thus crippling cells' ability to commit suicide. The net effect of crippling the cell suicide genes and then damaging the chromosomes was to allow more damaged chromosomes to survive instead of committing suicide.



In a normal fly, when a telomere is lost, only 10 percent to 20 percent of cells with such damage survive, with the rest killing themselves. But in flies whose suicide genes were crippled, up to 75 percent of cells survived despite lacking a telomere.



"Cells containing chromosomes with broken ends turn on a signal and Chk2 gets activated, and then that activates p53 which eventually leads to cell death," Golic says. "Chk1 also becomes activated and eventually activates p53."



Titen adds: "Chk1 and Chk2 were not previously known to be involved in cell death due to loss of a telomere."



The researchers found that if a damaged cell avoids suicide due to p53, Chk1 or Chk2, there is another way it can kill itself and avoid starting down the road to cancer.



This occurs when the damaged cell divides, and its progeny have the wrong number of chromosomes. The resulting genetic imbalance can cause cell suicide. Thus, telomere loss also is linked to this alternative form of cell suicide. The study shows for the first time that this type of cell death - which doesn't use p53 - is caused by gaining or losing copies of other important genes, Golic says.



Cells that bypass all of the protective suicide measures divide multiple times, accumulating more and more chromosomal abnormalities. In humans, such cells are likely to develop into cancer cells.







The study was funded by the National Institutes of Health.



University of Utah Public Relations

201 Presidents Circle, Room 308

Salt Lake City, Utah 84112-9017

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Source: Lee Siegel


University of Utah

Autotomy Reduces Immune Function And Antioxidant Defence

In their struggle for life, many animals have evolved a fascinating mechanism to avoid being eaten: sacrificing a body part.


When a prey animal is grasped by a predator, the body part is amputated so that the animal itself can escape. Despite the obvious short-term survival benefit, there are long-term costs like reduced lifespan. These costs were traditionally explained by reduced locomotion after limb loss.


We identified a novel type of cost, impaired immunity, which should make prey more vulnerable to parasites. Trying to escape from one enemy can therefore drive prey in the arms of another one.


Royal Society Journal Biology Letters


Biology Letters publishes short, innovative and cutting-edge research articles and opinion pieces accessible to scientists from across the biological sciences. The journal is characterised by stringent peer-review, rapid publication and broad dissemination of succinct high-quality research communications.


publishing.royalsociety/biologyletters

Adolescent Smokers Prone To Drug Abuse

It is common knowledge that smoking is a health risk but why do teens become addicted to smoking more easily than adults? In an evaluation for Faculty of 1000 Biology, Neil Grunberg looks into why adolescents are more prone to substance abuse.



Grunberg describes the study, published by Natividad et al. in Synapse journal, as "fascinating" and suggests it "may have implications to help understand why adolescents are particularly prone to drug abuse".



Nicotine increases the level of dopamine in the brain, a neurotransmitter that is responsible for feelings of pleasure and wellbeing. The study looked at dopamine levels in adolescent and adult rats after nicotine withdrawal. The authors found that the withdrawal signs (physical and neurochemical) seen in adolescent rats were fewer than those observed in adults.



The study provides previously unknown mechanisms as to why there are differences in nicotine withdrawal between adolescent and adult rats. The key here, as stated by Grunberg, is "age alters [neurological] systems and interactions relevant to nicotine".



The reason that adolescents are prone to drug abuse (in this case, nicotine) is that they have increased sensitivity to its rewarding effects and do not display the same negative withdrawal effects as adults do, due to an underdeveloped dopamine-producing system.



Since rats are not subject to cultural influences, "rat studies of nicotine ... have provided valuable insights that have led to practical behavioural and pharmacological interventions", says Grunberg.



The results of this study may not stop at nicotine. Grunberg continues, "these findings might also be relevant to other addictive and abuse drugs".



The full text of this article is available free for 90 days at f1000biology/article/d43fbwjsqtzb3f1/id/1166360



An abstract of the original article Nicotine withdrawal produces a decrease in extracellular levels of dopamine in the nucleus accumbens that is lower in adolescent versus adult male rats is at ncbi.nlm.nih/sites/entrez/19771590



Source: Steve Pogonowski


Faculty of 1000: Biology and Medicine

Whole-Cell Computer Simulations

Researchers have built a computer model of the crowded interior of a bacterial cell that - in a test of its response to sugar in its environment - accurately simulates the behavior of living cells.



The new "in silico cells" are the result of a collaboration between experimental scientists at the Max Planck Institute of Biology in Germany and theoretical scientists at the University of Illinois using the newest GPU (graphics processing unit) computing technology.



Their study appears in the journal PLoS Computational Biology.



"This is the first time that we're modeling entire cells with the complete contents of the cellular cytoplasm represented," said Illinois postdoctoral researcher and lead author Elijah Roberts. "We're looking at the influence of the whole cellular architecture instead of modeling just a portion of the cell, as people have done previously."



University of Illinois chemistry professor Zaida Luthey-Schulten, who led the research, had done molecular dynamics simulations of individual molecules or groups of molecules involved in information processing, but never of a system as large and complex as the interior of an entire cell.



Then in 2006 she saw a paper by Wolfgang Baumeister and his colleagues at Max Planck that located every one of a bacterium's ribosomes, its protein-building machines, inside the cell.



That image spurred Luthey-Schulten to think about modeling an entire cell, and she asked Baumeister and his colleague Julio Ortiz if they would repeat the study in Escherichia coli (E. coli), a bacterium that has been the subject of numerous molecular studies.



Once the new ribosome data were available, Roberts looked to other studies that described the size distribution of the rest of the molecules that take up space in the cell. By adding these to the ribosome data, he developed a three-dimensional model that showed the degree of "molecular crowding" in a typical E. coli cell.



Luthey-Schulten was amazed at how little "space" remained inside the cell, she said.



"I think, like everybody else, my perception of the cell up until Wolfgang and Julio's 2006 article had always been that it's a pretty big sack of water where a lot of chemical reactions occur," she said.



"But in fact there are a lot of obstacles in the cell, and that is going to affect how individual molecules move around and it's going to affect the reactions that occur."



Other researchers have begun studying the effects of molecular crowding on cellular processes, but never at the scale of an entire cell.



Those studying live cells can - by conducting fluorescence experiments - discover variations in the copy number of a particular protein in a population of cells. But they are less able to observe the microscopic details that give rise to such differences between genetically identical cells. Well-designed computer simulations of whole cells can track every reaction within the cells while also accounting for the influence of molecular crowding and other variations between cells, Luthey-Schulten said.
















For example, by running simulations on models of two E. coli strains, the researchers were able to see that "bacterial cell architecture does indeed affect the reactions that occur within the cells," Luthey-Schulten said. When sugar was present in its environment, a longer, narrower E. coli strain was able to ramp up production of a sugar-transporter protein much more quickly than a bigger strain, the researchers found. That difference had a lot to do with the distribution of molecules in each cell type, Roberts said.



The computer simulation also showed how molecular crowding influences the behavior of a molecule that, when it binds to DNA, shuts down production of the sugar-transporter protein. Even when it wasn't bound to DNA, this repressor remained close to the binding site because other molecules in the cell blocked its escape. These intracellular obstacles reduced its ability to diffuse away.



The new model is only a first step toward an accurate simulation of a whole working cell, the researchers said. The development of better models will rely on the work of those conducting research on actual cells. Their data provide the framework for improving computer models, Luthey-Schulten said, and offer a real-world test of the in silico cells' ability to recreate the behavior of living cells.


Notes:


Future studies will further develop the E. coli models and will focus on methane-generating archaeal microbes.



This research was supported by the Department of Energy Office of Science, the National Science Foundation and the Foundation Fourmentin-Guibert. Computational resources were provided by the NSF through the TeraGrid and the National Center for Supercomputing Applications, and also by the CUDA Center of Excellence at Illinois.



The paper: "Noise Contributions in an Inducible Genetic Switch: A Whole-Cell Simulation Study"



Source:

Diana Yates, Life Sciences Editor

University of Illinois at Urbana-Champaign

Scientists Demystify An Enzyme Responsible For Drug And Food Metabolism

For the first time, scientists have been able to "freeze in time" a mysterious process by which a critical enzyme metabolizes drugs and chemicals in food. By recreating this process in the lab, a team of researchers has solved a 40-year-old puzzle about changes in a family of enzymes produced by the liver that break down common drugs such as Tylenol, caffeine, and opiates, as well as nutrients in many foods. The breakthrough discovery may help future researchers develop a wide range of more efficient and less-expensive drugs, household products, and other chemicals. The scientists' findings were published in the journal Science on 12 November 2010.



Michael Green, an associate professor of chemistry at Penn State University and lead author of the study, explained that scientists have speculated for decades that, during the process of metabolizing chemicals in the human liver, enzymes in the family named P450 pass through a critical chemical phase-change called "Compound I," whereby an oxygen molecule is temporarily added. However, until now, no one had actually seen the process happen or even had proven that it existed. "This phase change happens quickly, and P450 just as quickly changes back to its original state," Green explained. "So the challenge was trapping the enzyme at the exact moment that it went through the Compound I stage." First, Green and his colleagues grew one of the P450 enzymes in E.coli - bacteria found in the human gut. They then developed a method to cool the enzyme at just the right rate - one one-thousandth of a second - to "freeze in time" the formation process of Compound I.



Green also explained that, while all humans have a gene responsible for making the P450 enzymes, different populations of humans vary in which version of the gene they carry, and thus, which version of P450 they produce. Such P450 variations lead to differences in the way people respond to particular drugs. "With a drug such as caffeine, for example, one population of people might be fast metabolizers, while another might metabolize the drug more slowly," Green explained. "Because the risk of caffeine-induced heart attack may be higher in slow metabolizers, the ability to actually take a snapshot of the phase changes of the P450 enzymes could help us to understand better how certain chemicals can affect people in vastly different ways."



Green's P40 research may also aid future scientific discoveries in the field of pharmacology. "Adverse drug-drug interactions are a well-known problem," Green explained. "The answer to why some people have bad interactions could be understood at the level of the P450 enzymes and their state changes. Now that we can see those state changes on a molecular level, a deeper investigation is finally possible."



Notes:


Green's co-author is Jonathan Little, who was an undergraduate student in Penn State's Department of Chemistry throughout the research study. Little is now a graduate student at the California Institute of Technology.



This research was supported by a grant from the National Science Foundation.



Source:

Barbara K. Kennedy

Penn State

Alternative To Embryonic Stem Cells Stem May Be Provided By Cells Found In Adult Hair Follicles

Having recently identified the molecular signature of these epidermal neural crest stem cells in the mouse, their research resolves conflicting scientific opinions by showing that these cells are distinctly different from other types of skin-resident stem cells/progenitors. Their work provides a valuable resource for future mouse neural crest stem cell research.



A report on the research from Dr. Maya Sieber-Blum's laboratory, co-authored by Yao Fei Hu, Ph.D., and Zhi-Jian Zhang, Ph.D., researchers in cell biology, neurobiology and anatomy at the Medical College, was published in a recent issue of Stem Cells: The International Journal of Cell Differentiation and Proliferation.



Epidermal neural crest stem cells are found in the bulge of hair follicles and have characteristics that combine some advantages of embryonic and adult stem cells, according to lead researcher, Maya Sieber-Blum, Ph.D., professor of cell biology, neurobiology & anatomy. Similar to embryonic stem cells, they have a high degree of plasticity, can be isolated at high levels of purity, and can be expanded in culture. Similar to other types of adult stem cells, they are readily accessible through a minimally invasive procedure and could lead to using a patient's own hair as a source for therapy without the controversy or medical issues of embryonic stem cells.



"We see the potential for cell replacement therapy in which patients can be their own donors, which would avoid ethical issues and reduce the possibility of tissue incompatibility," says Dr. Sieber-Blum.



The Medical College team in collaboration with Prof. Martin Schwab, director of the Brain Research Institute of the University of Zurich, recently injected these cells in mice with spinal cord injuries. According to the study, when grafted into the spine, the cells not only survived, but also demonstrated several desirable characteristics that could lead to local nerve replacement and re-myelination (restoration of nerve pathways and sheaths).



Neural crest stem cells generate a wide array of cell types and tissues and actually give rise to the autonomic and enteric nervous systems along with endocrine cells, bone and smooth muscle cells. The cells can be isolated from the hair follicle bulge as multipotent stem cells, and then expanded in culture into millions of cells without losing stem cell markers.



"We grafted the cells into mice that have spinal cord injuries and were encouraged by the results. The cells survived and integrated into the spinal cord, remaining at the site of transplantation and not forming tumors," Dr. Sieber-Blum says.



According to Dr. Sieber-Blum, subsets of the epidermal neural crest stem cells express markers for oligodendrocytes, the nerve-supporting cells that are essential for proper neuron function. She has been awarded a grant from the Biomedical Technology Alliance, a Milwaukee inter-institutional research group, to determine in collaboration with Brian Schmit, Ph.D., associate professor of biomedical engineering at Marquette University, if the grafts lead to an improvement of spinal reflexes in the injured spinal cord of mice.



Dr. Sieber-Blum points out that the cells may also be useful to treat Parkinson's disease, multiple sclerosis, Hirschsprung's disease, stroke, peripheral neuropathies and ALS. Certain defects of the heart, and bone defects (degeneration, craniofacial birth defects) could also be treated through neural crest stem cell replacement therapy. Together, these conditions affect over 11 million people today in the US and are estimated to annually cost more than $170 billion.






Contact: Toranj Marphetia


Medical College of Wisconsin

Adult Skin Cellsturned Into Muscle And Vice Versa At Stanford

In a study featured on the cover of the May issue of The FASEB Journal, researchers describe how they are able to reprogram human adult skin cells into other cell types in order to decipher the elusive mechanisms underlying reprogramming. To demonstrate their point, they transformed human skin cells into mouse muscle cells and vice versa. This research shows that by understanding the regulation of cell specialization it may be possible to convert one cell type into another, eventually bypassing stem cells.



"Regenerative medicine provides hope of novel and powerful treatments for many diseases, but depends on the availability of cells with specific characteristics to replace those that are lost or dysfunctional," said Helen M. Blau, Ph.D., the senior scientist involved in the study, Associate Editor of The FASEB Journal, Member of the Stem Cell Institute, and Director of the Baxter Laboratory in Genetic Pharmacology at Stanford. "We show here that mature cells can be directly reprogrammed to generate those necessary cells, providing another way besides embryonic stem cells or induced pluripotent stem cells of overcoming this important bottleneck to restoring tissue function."



The Stanford scientists sought to transform one specialized adult cell from one species into a different specialized adult cell of another species. To do this, they first used a chemical treatment to fuse skin and muscle cells together, producing cells that had nuclei from human skin cells and mouse muscle cells. By being encapsulated within the same cell wall, the human skin cells and mouse muscle nuclei could now "talk" to one another via chemical signals. Then, the scientists looked at the genes expressed from the human skin nuclei and mouse muscle nuclei. (This was possible because one cell type was human and the other was mouse, so the genes could be distinguished based on species differences.) After several experiments, they were able to induce the human skin nuclei to produce mouse muscle genes and induce the muscle nuclei to produce human skin genes - effectively transforming the cell from one type to the other.



"Reprogramming mature cells will likely complement the use of embryonic stem cells in regenerating tissues," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "By elucidating the regulators of reprogramming, as the Stanford group is doing, it may be possible to generate replacement cells in cases where stem cells are not present or not appropriate."



Source:
Cody Mooneyhan


Federation of American Societies for Experimental Biology

New Strategy To Create Genetically Modified Animals Reported By Penn Veterinary Medicine

Researchers at the University of Pennsylvania School of Veterinary Medicine have demonstrated the potential of a new strategy for genetic modification of large animals. The method employs a harmless gene therapy virus that transfers a genetic modification to male reproductive cells, which is then passed naturally on to offspring.



Ina Dobrinski, associate professor and director of the Center for Animal Transgenesis and Germ Cell Research at Penn Vet, and her colleagues introduced adeno-associated virus, AAV, to male germline stem cells in both goats and mice. The study showed that AAV stably transduced male germ line stem cells and led to transgene transmission through the male germ line.



The findings, available online in The FASEB Journal and in the February 2008 print edition, are the first report of transgenesis via germ cell transplantation in a non-rodent species, a promising approach to germ line genetic modification. It also demonstrates that germline transduction and germ cell transplantation in large animals provides an approach that is potentially less costly than microinjection and cloning, the traditional methods used to generate transgenic large animal models for biomedical research.



Researchers used mouse germ cells harvested from experimentally induced cryptorchid donor testes that were then exposed in vitro to AAV vectors carrying a green fluorescent protein transgene and transplanted to germ cell-depleted recipient testes, resulting in colonization of the recipient testes by transgenic donor cells.



When researchers mated these recipient males with wild-type females, 10 percent of offspring carried the gene originally introduced into the transplanted germ cells, meaning the genetic modification had been passed on. To broaden the approach to non-rodent species, AAV-transduced germ cells from goats were transplanted to recipient males in which endogenous germ cells had been depleted by fractionated testicular irradiation. Transgenic germ cells colonized recipient testes and produced transgenic sperm. When semen was used for in vitro fertilization, 10 percent of embryos were transgenic.



"Initially, the team used the established germ cell transplantation model in the mouse to investigate whether AAV-mediated transduction of germ cells was possible and could result in transgene transmission," Dobrinski said. "To broaden the applicability of the results for different mammalian species, the approach was then applied to a large animal species in which germ cell transplantation-mediated transgenesis would provide an important alternate approach to the generation of transgenic animal models for biomedical research."



Currently, somatic cell nuclear transfer or pronuclear injection is used to generate transgenic animals. These inefficient and difficult methods also carry a risk of producing offspring with developmental abnormalities. The use of retroviral or lentiviral vectors has been reported in rodents, but it requires that animals be handled and maintained under higher biosafety precautions that render this approach less practical for transgenesis in large animal species. In contrast, animals exposed to AAV can be maintained under standard husbandry conditions.



AAV is a dependent virus that carries no disease and causes only a very mild response from the immune system. Because AAV can infect both dividing and non-dividing cells and passes its genome, it is considered an excellent candidate for use in gene therapy.







The research was performed as a collaboration between Dobrinski, Ali Honaramooz, Susan Megee, Jinping Luo, Hannah Galantino-Homer, Mark Modelski, Fangping Chen and Wenxian Zeng of the Center for Animal Transgenesis and Germ Cell Research at the New Bolton Center of the Penn School of Veterinary Medicine; Fang Yang and P. Jeremy Yang of the Department of Animal Biology at Penn Veterinary Medicine; Margret Destrempes, Stephen Blash, David Melican, William Gavin, Yann Echelard and Susan Overton of GTC Biotherapeutics Inc.; and Sandra Ayres of the Tufts Cummings School of Veterinary Medicine.



The research was supported by a grant from the National Institute of Child Health and Human Development and the National Center for Research Resources.



Source: Jordan Reese


University of Pennsylvania

Shift Work And Metabolic Disorders

Scientists from Kiel and Odense/Denmark are currently jointly researching the influence that working shifts, the quality of sleep and nutrition has on metabolic disorders and gene activity. The Department of Human Biology in the Zoological Institute at Kiel University, the Institute of Human Genetics at the University Medical Center Schleswig-Holstein, Campus Kiel and the University of Southern Denmark in Odense are participating in the new project: "Sleep, work and their consequences for human metabolic disorders". The researchers are receiving support amounting to EUR 730,000 over a period of three years from the European Union as part of the INTERREG 4A South Denmark-Schleswig-K.E.R.N. programme, using funds from the European Regional Development Fund. The long-term objective of this study is to develop preventative measures in order to reduce the risk of metabolic and sleep disorders developing in future.


People who work shifts are not able to comply with the natural sleep/wake rhythm based on the cycle of day and night. Their internal body clock becomes unbalanced. The consequences of this can be a variety of metabolic disorders which, on a long-term basis, can be accompanied by a range of illnesses, psychological disorders and even the inability to work. In order to be able to investigate the extent of the changes to the human body and its cells which result from shift work, pairs of twins from Denmark are being examined using molecular-biological methods. From each pair, one twin works shifts. According to the Kiel human geneticist, Dr. Ole Ammerpohl, "The advantage of examining identical twins is that both are practically genetically alike and the effects of lifestyle can be identified more easily. That is why it is essential to work together with the national Danish twins register, which has been analysing twins with regard to medical and professional aspects for many years."


The effects of working shifts may well be far more fundamental than previously assumed. They may have a direct impact on our genetic make-up and the genes contained within this material. "Gene activity is controlled by small switches on the DNA, known as DNA methylation", explains Ammerpohl. "This DNA methylation adjusts to suit changes in environmental conditions and can even be passed on to subsequent generations."


Alongside shift work itself, nutritional and sleeping patterns also aid the development of metabolic disorders. Therefore the project does not only include DNA methylation and genetic variations, it also covers the twins' nutritional behaviour, the quality of sleep obtained as well as hormone and blood counts (blood sugar, blood lipids, etc.). For example, whether the levels of the stress-hormone "cortisol" change in people as a result of working shifts is being tested. All the features mentioned above are placed in relation to each other at the university in Odense and evaluated using special mathematical models.


Right up until a few generations ago, people got up at daybreak and went to bed when it got dark. "In order to adjust to this, our bodies have evolved over centuries to develop a sophisticated system of transmitters which control the sleep-wake cycle and enable the body to regenerate sufficiently", explains Professor Manuela Dittmar from Kiel University. However, over the last few decades our lifestyles have changed drastically. Working hours are no longer based on how long the day lasts. "More and more people are required to work shifts. The consequences for those affected include a higher incidence of typical civilisation diseases right up to burn-out syndrome and early disability", according to Dittmar.


Source: Christian-Albrechts-Universitaet zu Kiel, AlphaGalileo Foundation.