Pulmonary Fibrosis Polymorphism Identified

A University of Colorado at Denver-led team found a new polymorphism that massively increases its carriers' risk for two related scarring disorders of the lung: idiopathic pulmonary fibrosis and familial interstitial pneumonia. The variant, which is in a regulatory region of the mucin gene, was present in 20 percent of the general population, but in more than half of all individuals with idiopathic pulmonary fibrosis and familial interstitial pneumonia. The chances of having either disorder was increased roughly eightfold in heterozygotes and more than 20-fold in homozygotes. Individuals with the variant have excess mucus; how such excess mucus leads to scarring is not yet clear, but the authors said that there are "several biologically plausible mechanisms" that they plan to investigate, including the possibility that excess mucus traps particles that lead to lung scarring, and that it compromises the mucosal immune system. The work was published in the April 21, 2011, issue of The New England Journal of Medicine.

The Workings of an ADHD Gene

Scientists at the Korea Advanced Institute of Science and Technology have characterized a genetic polymorphism that is associated with attention deficit hyperactivity disorder (ADHD). The authors genotyped about 200 children with ADHD and 200 controls to test previously identified SNPs in areas near known neuronal proteins, and identified a polymorphism within the protein GIT-1 as associated with ADHD. GIT-1 knockout mice were hyperactive, and had memory problems and brain activity patterns that were similar to those of children with ADHD. Those symptoms were improved by amphetamines, which are also used to treat children with ADHD. The authors said that lack of GIT1 may lead to ADHD by changing the brain's balance of excitation and inhibition. Their results were published in the April 17, 2011, online issue of Nature Medicine.

Novel Depression Target

The signaling of brain-derived neurotrophic factor and its receptor, TrkB, play a role in depression by altering brain reward circuits. But small-molecule inhibitors of TrkB have been hard to come by, partly because both the receptor and its ligands are large. Now, researchers from Columbia University and the French Universite de Strasbourg have used a bioinformatics approach to identify a small-molecule inhibitor of TrkB signaling. Mice treated with the molecule showed reduced anxiety and and depression-like behaviors "on a variety of tests predictive of anxiolytic and antidepressant properties in humans." The authors said their compound "may be a valuable tool for studying BDNF/TrkB signaling and may constitute a lead compound for developing the next generation of therapeutic agents for the treatment of mood disorders." The findings appeared in the April 18, 2011, issue of the Journal of Clinical Investigation.

Hippo for Hearts

Flies, unlike mammals, can regenerate their heart muscles even as adults, but manage to do so without ending up with overly huge hearts under normal circumstances. In flies, this ability to divide is due to the activity of the Hippo pathway, which controls organ size in general. Now, researchers from the Texas A&M System Health Sciences Center have dissected the mammalian equivalent of this pathway. By selectively inactivating different parts of the signaling pathway, they were able to keep heart cells dividing, leading to animals with hearts that were more than twice as big as normal. The mouse version of the Hippo pathway appears to interact with the developmental regulatory gene Wnt. The work answers basic questions about how heart size is controlled, and suggests that targeting the mammalian equivalent of the Hippo pathway may offer possibilities for heart regeneration. It was published in the April 22, 2011, issue of Science.

Reperfusion Rescue

After a heart attack or stroke – and, despite surgeons' best efforts, during surgery – tissue damage occurs twice: first due to ischemia, or low oxygen, then due to reperfusion injury. Reperfusion injury results from activation of the innate immune system and subsequent inflammation when blood flow is restored. Researchers from Leicester University have reported that by blocking the activity of one particular protease, MASP-2, they were able to reduce the tissue damage due to reperfusion injury by more than 50 percent. Importantly, the treatment was effective even when given 12 hours after ischemia and reperfusion, which greatly improves its clinical outlook. MASP-2 is a proinflammatory protein, which activates the innate immune system. Seattle-based Omeros Corp., which has licensed the rights to the findings, is currently gearing up for clinical trials of a MASP-2 antibody. The work was published in the April 18, 2011, issue of the Proceedings of the National Academy of Sciences.

Senseless Bacteria

During an infection, bacteria turn virulent only when their numbers are sufficient to have a fighting chance against the immune system. For this reason, blocking the sensors that bacteria use to sense their concentration is one potential strategy to render infections harmless. Researchers from Princeton University reported they have found a method of interrupting bacterial chats that rely on one type of sensor. Their molecule works by binding to the two-part sensor protein and changing its conformation so that the two parts interact with each other, rather than binding to their signaling molecules. The authors said their strategy could be "broadly useful" for inhibiting receptors with multiple parts, or domains. The work was published in the April 22, 2011, issue of Molecular Cell.

ENCODE Consortium Releases User's Guide

Knowing a DNA sequence, as many a researcher has figured out over the past decade, is not terribly useful without an idea of what that DNA sequence does in the cell – and while protein-coding sequences are relatively easy to identify, other genome stretches have remained mysterious. The Encyclopedia of DNA Elements or ENCODE Consortium has the goal of figuring out what every last useful snippet of DNA actually does, by using statistical and bioinformatics methods in addition to classical experimental techniques. The consortium has published a User's Guide that "provides an overview of the complete project and the resources it is generating, as well as examples to illustrate the application of ENCODE data as a user's guide to facilitate the interpretation of the human genome." The guide appeared in the April 19, 2011, issue of PLoS Biology.

Gut Bacteria Classification Easy as 1, 2, 3

An international consortium of scientists, led by researchers from the Free University of Brussels, has shown that though there are many species of gut bacteria, those bacteria generally cluster into three types – bacteroides, Prevotella and Ruminococcus. Moreover, in a given person, those three types tend to combine in one of three different patterns. Some classes of bacteria are much more frequent in some patterns than others, but the authors stressed some rare bacterial species appear to be some of the busiest, judging by the metabolites they produce. Which pattern an individual has does not appear to depend on their age, race, gender or geographic location; but the scientists found several gut bacterial genes that correlated with age and body mass index, "hinting," they wrote, "at a diagnostic potential of microbial markers." The work was published in the April 20, 2011, advance online edition of Nature.

RORing at Autoimmunity

Researchers from the Scripps Institute discovered a compound that may be able to damp down autoimmune responses of multiple sclerosis without suppressing the immune system in general, which could improve treatments for autoimmune disorders. The authors targeted two distinct retinoic acid relate orphan receptors on TH17 cells, a relatively recently identified subtype of T helper cell that appears to play a larger role in inflammation and autoimmunity than in antibacterial or antiviral defense. The scientists showed that inhibiting the ROR receptors prevented TH17 cell development, and reduced the severity of symptoms in mice with experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. They said their data showed their compound and its derivatives "may represent a novel class of superior drugs" to treat autoimmunity – and, possibly, metabolic disorders. The work appeared in the April 17, 2011, advance online edition of Nature.

Genome Sequencing Gets Fast Enough to Matter

Researchers from Washington University in St Louis reported that in sequencing the whole genome of an acute promyelocytic leukemia patient, they were able to identify a mutation within seven weeks that changed the treatment plan for that patient. The authors showed that although the patient did not have the classical gene fusion of acute promyelocytic leukemia, she did have another fusion that made her a candidate for a specific type of targeted treatment, rather than a stem cell transplant. By using what they described as a "'movable firewall' that maintains patient anonymity within the entire research team, but allows the research team to communicate medically relevant information to the treating physician," the authors also showed some of the practical privacy implications of whole genome sequencing. The work was published in the April 20, 2011, issue of the Journal of the American Medical Association.

Atherosclerosis: Monocytes, Not Macrophages

Researchers from Mount Sinai School of Medicine discovered how cholesterol-lowering therapy drives back plaque. In ApoE knockout mice, they reported that restoring ApoE via gene therapy reduced the macrophage content of plaques; macrophages are immune system cells with high fat content that make up the major components of plaque. The macrophages did not actively leave the plaques; instead, reduced recruitment by monocytes, coupled with cell death, lowered their numbers over time. The authors wrote their data "suggest that therapies to inhibit monocyte recruitment to plaques may constitute a more viable strategy to reduce plaque macrophage burden" than trying to target macrophages directly. That conclusion was published in the April 18, 2011, issue of the Journal of Clinical Investigation.

– Anette Breindl, Science Editor