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Archive - Mar 9, 2011

Mutation Identified That Would Likely Increase Transmissibility of H1N1 Influenza

In the fall of 1917, a new strain of influenza swirled around the globe. At first, it resembled a typical flu epidemic: Most deaths occurred among the elderly, while younger people recovered quickly. However, in the summer of 1918, a deadlier version of the same virus began spreading, with disastrous consequence. In total, the pandemic killed at least 50 million people — about 3 percent of the world’s population at the time. That two-wave pattern is typical of pandemic flu viruses, which is why many scientists worry that the 2009 H1N1 (“swine”) flu virus might evolve into a deadlier form. H1N1, first reported in March 2009 in Mexico, contains a mix of human, swine, and avian flu genes, which prompted fears that it could prove deadlier than typical seasonal flu viruses. However, the death toll was much lower than initially feared, in large part because the virus turned out to be relatively inefficient at spreading from person to person. In a new study from MIT, researchers have identified a single mutation in the H1N1 genetic makeup that would likely allow it to be much more easily transmitted between people. The finding, reported on March 2, 2011 in the journal PLoS ONE, should give the World Health Organization, which tracks influenza evolution, something to watch out for, said Dr. Ram Sasisekharan, senior author of the paper.“There is a constant need to monitor the evolution of these viruses,” said Dr. Sasisekharan, the Edward Hood Taplin Professor and director of the Harvard-MIT Division of Health Sciences and Technology. Some new H1N1 strains have already emerged, and the key question, Dr. Sasisekharan added, is whether those strains will have greater ability to infect humans.

Sequencing Shows CREBBP Mutations in Relapsing Leukemia

Despite dramatically improved survival rates for childhood acute lymphoblastic leukemia (ALL), relapse remains a leading cause of death from the disease. Work led by St. Jude Children's Research Hospital investigators identified mutations in a gene named CREBBP that may help the cancer resist steroid treatment and fuel ALL's return. CREBBP plays an important role in normal blood cell development, helping to switch other genes on and off. In this study, researchers found that 18.3 percent of the 71 relapsed-ALL patients carried alterations in the DNA sequence of CREBBP. In contrast, the gene's sequence was changed in just one of the 270 young leukemia patients whose cancer did not return. Investigators say the gene is a potential indicator of relapse risk because of the high frequency of CREBBP mutations in relapsed patients and evidence the changes persisted from diagnosis or emerged at relapse from subpopulations of leukemia cells present from the beginning. Researchers also found evidence the changes occur in important regulatory regions of the gene and affect cell function, including how cancer cells respond to the steroids that play an important role in cancer treatment. The work appears in the March 10 issue of Nature. "This study gives us further evidence that detailed genomic studies can identify important mutations that influence tumor response to treatment," said Dr. Charles Mullighan, assistant member of the St. Jude Department of Pathology. Dr. Mullighan and Dr. Jinghui Zhang, an associate member of the St. Jude Department of Computational Biology, are co-first authors of the ALL article. Dr. Mullighan is also the corresponding and senior author. ALL is the most common childhood cancer. While ALL cure rates have climbed to 90 percent, the disease is often deadly if it returns.

Calcium Channel Defect Causes Deafness, Irregular Heartbeat

Ten years ago, scientists seeking to understand how a certain type of cell feature called an L-type calcium channel worked created a knockout mouse missing both copies of the CACNA1D gene. The CACNA1D gene makes a protein that lets calcium flow into a cell, transmitting important instructions from other cells. The knockout mice lived a normal life span, but their hearts beat slowly and arrhythmically. They were also completely deaf. On March 9, 2011, at the 55th Annual Biophysical Society Meeting in Baltimore, an international team lead by Dr. Hanno Bolz of the University of Cologne in Germany reported identification of a mutation on the CACNA1D gene affecting two families in Pakistan. The altered gene adds one extra amino acid to the middle of the protein, which is more than 2,000 amino acids in length. The result is that family members with two copies of the mutated gene are not only deaf, but also have an irregular heartbeat. "Their heart beats slowly, dropping below 30 beats a minute during sleep," said Dr. Joerg Striessnig, professor at the University of Innsbruck in Austria and one of the study’s senior authors. The researchers analyzed the family's mutation and determined that it does not destroy the protein, said Dr. Striessnig. "Normally, part of the protein acts like a hinge to open the calcium channel once the cell gets stimulated. The mutated protein still sits in the cell's surface membrane where it should be, but the hinge does not open the channel," he said. "It's not only interesting for medicine but also for understanding how these channels work as molecular machines." [Press release]

How Scientists Identified Anthrax Strain in 2001 Letter Attacks

It took nearly a decade before University of Maryland researchers were allowed to talk about their work identifying the anthrax strain used in the 2001 deadly letter attacks. But now, they and the other key members of the high-powered science team have published the first account of the pioneering work, which launched the new field of "microbial forensics" and gave bioterrorism investigators a way to "fingerprint" bacteria. An article published online on March 7, 2011, in PNAS details the multi-institutional research that the FBI ultimately used to track anthrax-laden letters back to test tube number RMR-1029 at a lab in Fort Detrick, Maryland. University of Maryland bioinformatics experts co-authored the article and conducted the computational analysis that detected four genetic mutations that together comprised a unique signature of a particular colony of anthrax bacteria. The FBI subsequently determined this colony was found only in that Ft. Detrick test tube. The Maryland researchers have since developed their work into a genetic 'fingerprinting' tool that is available online to law enforcement seeking to track down other microbial suspects. "We found unique bio-markers to help investigators track down the source of the anthrax," said Dr. Steven Salzberg, director of the University of Maryland Center for Bioinformatics and Computational Biology (CBCB). "At first the tiny mutations were elusive. We thought we'd pieced together the 'jigsaw puzzle' of data very neatly, until we ended up with a few oddball bits left over. When we looked more closely, we found an extra copy of a critical gene." "Fortunately, anthrax bacteria mutate relatively slowly, so the material in this colony developed these small distinctive mutations that resulted in physically distinct characteristics," explained Dr. Mihai Pop, Dr.

Drug Halts Progression of Parkinson’s Disease in Mice

In a major breakthrough in the battle against Parkinson's disease, a research team at the University of Colorado School of Medicine has discovered a drug (phenylbutyrate) that stops the progression of the degenerative illness in mice and is now being tested in humans. "Drugs currently used to treat Parkinson's disease just treat symptoms; they do not stop the disease from getting worse," said senior author Dr. Curt Freed, who heads the division of Clinical Pharmacology and Toxicology at the CU School of Medicine. "We've now discovered that we can prevent the progression of the disease by turning on a protective gene in the brain." The results were published online on March 3, 2011, in the Journal of Biological Chemistry. Lead author Dr. Wenbo Zhou, Assistant Professor of Medicine, and Dr. Freed, a national pioneer in Parkinson's research, and colleagues have found that the drug phenylbutyrate turns on a gene that can protect dopamine neurons in Parkinson's disease. The gene, called DJ-1, can increase production of antioxidants like glutathione to reduce the debilitating effects of excess oxygen in brain cells. In addition, activating DJ-1 helps cells eliminate abnormal proteins that otherwise accumulate and kill brain cells. Dopamine neurons are particularly susceptible to too much oxygen and abnormal protein deposits. Parkinson's disease is caused by dying midbrain dopamine neurons. Dr. Zhou and Dr. Freed have studied the DJ-1 gene since 2003 when a European group discovered that mutations in DJ-1 could cause Parkinson's disease. The Colorado scientists immediately started work to see why the gene was so important and have published a series of papers on the subject since 2005. But to convert their findings into a practical treatment for Parkinson's disease, they needed to find a drug to turn on the DJ-1 gene.