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Archive - Feb 2015

February 8th

New Paradigm Established for Tissue-Biomaterial Interactions; Personalized Precision Medicine Approach Developed for Tissue Adhesive Used in Surgery; Effectiveness Not Organ-Dependent, But Disease-Type and State-Dependent

After undergoing surgery to remove diseased sections of the colon, up to 30 percent of patients experience leakage from their sutures, which can cause life-threatening complications. Many efforts are under way to create new tissue glues that can help seal surgical incisions and prevent such complications. Now, a new study from MIT reveals that the effectiveness of such glues hinges on the state of the tissue in which they are being used. The MIT researchers found that a sealant they had previously developed worked much differently in cancerous colon tissue than in colon tissue inflamed with colitis. The finding suggests that for this sealant, or any other kind of biomaterial designed to work inside the human body, scientists must take into account the environment in which the material will be used, instead of using a “one-size-fits-all” approach, according to the researchers. “This paper shows why that mentality is risky,” says Dr. Natalie Artzi, a Research Scientist at MIT’s Institute for Medical Science and Engineering (IMES) and senior author of a paper describing the findings that was published in the January 28, 2015 issue of Science Translational Medicine. The title of this paper is “Regulation of Dendrimer/Dextran Material Performance by Altered Tissue Microenvironment in Inflammation and Neoplasia.” Dr. Artzi is also a Professor at Harvard Medical School and a Researcher at the Harvard-MIT Division for Health Sciences and Technology. In addition, she is Assistant Professor, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School. “We present a new paradigm by which to design and examine materials.

February 8th

Five-Year Effort Reveals the Cellular Origami of Chromatin Looping in Human DNA; Same Loops Preserved Over 100 Million Years of Evolution; Largest Loops Seen Only in Women; Folding Drives Function; Thousands of Unknown Hidden Switches Found

The ancient Japanese art of origami is based on the idea that nearly any design--a crane, an insect, a samurai warrior--can be made by taking the same blank sheet of paper and folding it in different ways. The human body faces a similar problem/challenge. The genome inside every cell of the body is identical, but the body needs each cell to be different--an immune cell fights off infection; a cone cell helps the eye detect light; the heart’s myocytes must beat endlessly. In a remarkable article published in the December 18, 2014 issue of Cell, researchers at Baylor College of Medicine, Rice University, the Broad Institute of MIT and Harvard, and Harvard University describe the results of a five-year effort to map, in unprecedented detail, how the 2-meter-long human genome folds inside the nucleus of a cell. The title of the article is, “A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping.” The results show that the cell--like a microscopic origamist--modulates its function by folding the genome into an almost limitless variety of shapes. A centerpiece of the new study is the first reliable catalog of loops spanning the entire human genome. For decades, scientists have examined the regions in the close vicinity of a gene to understand how the gene is regulated. But as the genome folds, sequences initially far from a gene loop back and come in contact with those nearby elements. Looping has been a blind spot for modern biology. “For over a century, scientists have known that DNA forms loops inside of cells, and that knowing where the loops are is incredibly important,” said co-first author Dr. Suhas Rao, a researcher at the Center for Genome Architecture at Baylor.

Epigenetics Stunner! Non-DNA-Coded Changes Can Be Transmitted for More Than 25 Generations by Mobile dsRNA That Transforms Germ Cells; Entirely New and Different Mechanism of Much Faster Evolution Is Possible; Perhaps Key to Treating Genetic Diseases

For more than a century, scientists have understood the basics of inheritance: if good genes help parents survive and reproduce, the parents pass those genes along to their offspring. And yet, recent research has shown that reality is much more complex: genes can be switched off, or silenced, in response to the environment or other factors, and sometimes these changes can be passed from one generation to the next. The phenomenon has been called epigenetic inheritance, but it is not well understood. Now, University of Maryland geneticist Dr. Antony Jose and two of his graduate students are the first to figure out a specific mechanism by which a parent can pass silenced genes to its offspring. Importantly, the team found that this silencing could persist for multiple generations—more than 25, in the case of this study. The research, which was published online on February 2, 2015 in PNAS, could transform our understanding of animal evolution. Further, it might one day help in the design of treatments for a broad range of genetic diseases. The title of the PNAS article is, "“Double-Stranded RNA Made in C. elegans Neurons Can Enter the Germline and Cause Transgenerational Gene Silencing.” “For a long time, biologists have wanted to know how information from the environment sometimes gets transmitted to the next generation,” said Dr. Jose, an Assistant Professor in the University of Maryland Department of Cell Biology and Molecular Genetics. “This is the first mechanistic demonstration of how this could happen. It’s a level of organization that we didn’t know existed in animals before.” Dr. Jose and graduate students Sindhuja Devanapally and Snusha Ravikumar worked with the roundworm Caenorhabditis elegans, a species commonly used in lab experiments.

Duke Study Shatters Conventional Thinking on Sugar Metabolism; Fifth Hexokinase Identified; Links to Hyperglycemia and Gestational Diabetes; Stunning Result May Lead to Test for At-Risk Women; Understanding May Help Stem Global Epidemic of Diabetes

For at least 40 years, scientists who study how the body metabolizes sugar have accepted one point: there are four enzymes that kick-start the body’s process of getting energy from food. The discovery of these four catalysts for energy production, called hexokinases, generated more research into how the body metabolizes carbohydrates, and how interfering with those enzymes through medications could help manage metabolic disorders such as diabetes. But this biochemical foursome may not deserve all of the credit. According to research by scientists at Duke University and Northwestern, the hexokinase team actually has a fifth player. The findings were published online on February 4, 2015 in Nature Communications. “This swims against the past 40 years of research and what we thought we knew,” said Tim Reddy, Ph.D., a senior author of the study and Assistant Professor of Biostatistics and Bioinformatics at Duke. “Hexokinases are critical to basically all of our energy production. Finding a fifth one opens the door to more study into how we metabolize sugar, as well as genetic links to metabolic disorders.” The new protein is called HKDC1, and the researchers report that this enzyme may be a genetic predictor for whether an expectant mother develops hyperglycemia, or excess blood sugar, during pregnancy. Hyperglycemia is a potentially harmful environment for a growing fetus and can contribute to obesity and diabetes later in the child’s life. While at least 4 percent of pregnant women develop diabetes during pregnancy, as many as 400,000 women each year in the U.S. have gestational hyperglycemia, which equals about 10 percent of expectant mothers.

Type 1 Diabetes Onset Linked to Changes in Gut Microbiota in Unique and “Compelling” Prospective Study at Broad, MIT, MGH, and Harvard

In the largest longitudinal study of the microbiome to date, researchers from the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and the DIABIMMUNE Study Group have identified a connection between changes in gut microbiota and the onset of type 1 diabetes (T1D). The study, which followed infants who were genetically predisposed to type 1 diabetes, found that onset, for those who developed the disease, was preceded by a drop in microbial diversity, including a disproportional decrease in the number of species known to promote health in the gut. These findings, which were published online on Februar 5, 2015 in Cell, Host & Microbe, could help pave the way for microbial-based diagnostic and therapeutic options for those with T1D. The human microbiome, which consists of the trillions of microorganisms (bacteria, viruses, and other assorted “bugs”) that reside in our bodies, has become an area of growing interest to the medical community as researchers have begun to probe the role it plays in human health and disease. While most bugs in our microbiome are harmless, and even beneficial, changes in the microbiome (and in the interactions microbial species share with their human hosts) have been linked to various disease states, including diabetes and Inflammatory Bowel Disease (IBD). To explore the possible connection between changes in the microbiome and type 1 diabetes, a team led by Dr. Ramnik Xavier, M.D., an Institute Member of the Broad Institute and Chief of Gastroenterology at MGH, followed 33 infants (out of a much larger cohort of Finnish and Estonian children) who were genetically predisposed to T1D. From birth to age 3, the team regularly analyzed the subjects’ stool samples, collecting data on the composition of their gut microbiome.

Anorexia Study Suggests Eating Disorders Are “Not About Superficial Body Image Concerns or the Result of Bad Parenting;" "They Represent Real Biological Effects of Environmental Impacts in Affected People, Which Then Get Locked in by Too Much Dieting”

A new study led by Howard Steiger, Ph.D., head of the Douglas Mental Health University Institute Eating Disorders Program (EDP), in Montreal, Canada, in collaboration with Dr. Linda Booij, a researcher with Sainte-Justine Hospital and an Assistant Professor at Queen's University where?, is the first to observe effects suggesting that the longer one suffers from active anorexia nervosa (AN), the more likely he or she is to show disorder-relevant alterations in DNA methylation. When methylation is altered, gene expression is also altered, and when gene expression is altered, the expression of traits that are controlled by those genes is also changed. In other words, altered methylation can produce changes in emotional reactions, physiological functions, and behaviors. A report to be published in the International Journal of Eating Disorders, entitled "DNA Methylation in Individuals with Anorexia Nervosa and in Matched Normal-Eater Controls: A Genome-Wide Study," is showing chronicity of illness in women with AN to be associated with more pronounced alteration of methylation levels in genes implicated in anxiety, social behavior, various brain and nervous system functions, immunity, and the functioning of peripheral organs. "These findings help clarify the point that eating disorders are not about superficial body image concerns or the result of bad parenting. They represent real biological effects of environmental impacts in affected people, which then get locked in by too much dieting," says Dr. Steiger, Chief of the Eating Disorders Program at the Douglas Institute and a Professor of Psychiatry at McGill University in Montreal. "We already know that eating disorders, once established, have a tendency to become more and more entrenched over time.

February 7th

Monell Center Awarded Grant to Study Role of Nasal Airflow Obstruction in Loss of Smell (Anosmia)

Monell Center scientist Kai Zhao, Ph.D., is principal investigator on a $1.5-million, 4-year grant from the National Institute on Deafness and Other Communication Disorders (NIDCD), part of the National Institutes of Health, to further develop clinical methodology that can predict the path of air flow through a person’s nasal passages. The methodology may someday help physicians evaluate treatment outcomes for patients undergoing surgery to reverse nasal obstruction and associated loss of smell (anosmia). “Our proposed research intends to validate a clinical tool that can determine whether blockage of nasal airflow contributes to a patient’s smell loss,” said Dr. Zhao, a biological engineer at the Monell Center (Advancing Discovery in Taste and Small) in Philadelphia, Pennsylvania. “This knowledge will assist both patients and clinicians in planning effective treatment options and potentially save millions of dollars in healthcare costs each year by eliminating unnecessary surgeries.” The project adds to the Monell Center’s expanding list of research focused on anosmia, the clinical term for lack of the sense of smell. Anosmia has several causes, including physical nasal obstruction due to chronic nasal sinus disease. Such obstruction, which can be caused by inflamed tissues, polyps, or other physical causes, is thought to block airflow, thus preventing odor molecules from reaching smell receptors high inside the nose. Approximately one quarter of anosmia cases are related to chronic nasal sinus disease, which affects an estimated 30 million people in the United States each year, making it one of the country’s most common medical conditions. Patients with nasal sinus disease often report congestion and accompanying feelings of airflow blockage or obstruction. However, in earlier studies, Dr.

Plentiful Liver-Like Hepatocytes Grown from iPSCs; Used to Develop and Test Candidate Anti-Malaria Drugs

In 2008, the World Health Organization (WHO) announced a global effort to eradicate malaria, which kills about 800,000 people every year. As part of that goal, scientists are trying to develop new drugs that target the malaria parasite during the stage when it infects the human liver, which is crucial because some strains of malaria can lie dormant in the liver for several years before flaring up. A new advance by MIT engineers could aid in these efforts. The researchers have discovered a way to grow liver-like cells from induced pluripotent stem cells (iPSCs). These cells can be infected with several strains of the malaria parasite and respond to existing drugs the same way that mature liver cells taken from human donors do. Such cells offer a plentiful source for testing potential malaria drugs because they can be made from skin cells. New drugs are badly needed, because some forms of the malaria parasite have become resistant to existing treatments, says Dr. Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology (HST) and Electrical Engineering and Computer Science at MIT. "Drug resistance is emerging that we are continually chasing. The thinking behind the call to eradication is that we can't be chasing resistance and distributing bed nets to protect from mosquitoes forever. Ideally, we would rid ourselves of the pathogen entirely," says Dr. Bhatia, who is also a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES). These cells, described online on February 5, 2015 in an open-access article in Stem Cell Reports, could also allow scientists to test drugs on cells from people with different genetic backgrounds, who may respond differently to malaria infection and treatment.

After Blood Meal, Mosquitoes Ramp Up Immune System in Anticipation of Plasmodium Parasite

If you were about to enter a crowded subway during flu season, packed with people sneezing and coughing, wouldn't it be helpful if your immune system recognized the potentially risky situation and bolstered its defenses upon stepping into the train? According to a new study by University of Pennsylvania (Penn) and Imperial College London researchers, the mosquito immune system does something very similar. After ingesting a meal of blood, mosquitoes ramp up production of immune system proteins that help fight off the parasites that blood might contain. "This appears to be a new mechanism by which the mosquito is anticipating a parasite infection," said Dr. Michael Povelones, an Assistant Professor in Penn's School of Veterinary Medicine, who co-authored the study. Dr. Povelones collaborated on the work, published in the December 2014 issue of the Journal of Innate Immunity, with Imperial College London researchers Dr. Leanna M. Upton, a research associate, and Dr. George K. Christophides, a Professor and Chair of Infectious Diseases and Immunity. Dr. Povelones has spent many years studying the interplay between mosquitoes and parasites. While it's easy to think about mosquitoes as a mere portal for shuttling malaria and other diseases from one person to another, the insects themselves have their own immune response to infection. A greater understanding of how mosquitoes naturally fight off infection could offer a strategy for preventing humans from getting infected with those same pathogens. "With malaria and other vector-borne diseases, we're faced with problems of not having effective vaccines, [of] drug-resistant parasites, and [of] insecticide-resistant vectors. But, as it turns out, mosquitoes do a great job of controlling infection in their own bodies," said Dr. Povelones.

Salamander & Lungfish Studies Offer Clues to Evolution of Hearing

Lungfish and salamanders can hear, despite not having an outer ear or tympanic middle ear. These early terrestrial vertebrates were probably also able to hear 300 million years ago, as shown in a new study by Danish researchers. Lungfish and salamander ears are good models for different stages of ear development in these early terrestrial vertebrates. Two new studies, published online in the Proceedings of the Royal Society B (February 4, 2015) and The Journal of Experimental Biology (February 1, 2015), show that lungfish and salamanders can hear, despite not having an outer ear or tympanic middle ear. The study therefore indicates that the early terrestrial vertebrates were also able to hear prior to developing the tympanic middle ear. The research findings thus provide more knowledge about the development of hearing 250-350 million years ago. The physical properties of air and tissue are very different, which means in theory that up to 99.9% of sound energy is reflected when sound waves reach animals through the air. In humans and many other terrestrial vertebrates, the ear can be divided into three sections: the outer ear, the middle ear, and the inner ear. The outer ear catches sound waves and directs them into the auditory canal. In the middle ear, pressure oscillations in the air are transferred via the tympanic membrane (eardrum) and one or three small bones (ossicles) to fluid movements in the inner ear, where the conversion of sound waves to nerve signals takes place. The tympanic middle ear improves the transfer of sound energy from the surroundings to the sensory cells in the inner ear by up to 1,000 times, and is therefore very important for hearing in terrestrial vertebrates.