Neurology:
Huntington's Defects Manifest Far from Damaged Brain Tissue
Public Health:
Sugary Drinks Raise Risk of Obesity, Type 2 Diabetes
Neuromuscular Research:
Action Uncovered in Mutant Protein's Link to Nerve Cell Death in ALS
Leadership
Brugge Named Chair of Cell Biology
Knipe to Lead Graduate Program in Virology
Armenise Program:
Postgenome Technology Illuminates Cancer Biology at Eighth Armenise Symposium
Protein Reveals How a Growing Axon Steers
Genetic Variation Among People May Be Ten Times Higher than Previously Thought
Compound Fends Off Stroke Damage
Novel Drug Design Apporach Aims at Resistant Bacteria
Integrated Gradaute Program Created in Life Sciences
Innovators of Tomorrow
Center to Probe Immune Tolerance in Type 1 Diabetes
SPORE Grant Awarded in Ovarian Cancer Research
Broad Breaks Ground for New Building
Named Professorships Approved
In Memoriam:
Edward Frank
Cultural Competence May Limit Stereotyping
CDC Overhauls Organization, Shifts Toward Preparedness
Protein Reveals How a Growing Axon Steers
The growth cone of a developing axon spiders its way to new connections, guided by a landscape full of chemical cues that either attract or repulse. At the cone's tip is a tendril mass of actin that pushes ahead, groping for cues with its filopodia. At the cone's tail is a growing line of microtubule piping that serves as the core of the burgeoning axon.
The microtubule body of a growing Drosophila axon is topped, like cotton on a swab, with a bulb of actin filopodia that soak up directional signals. These cues trigger enzymes located at the junction of the bulb and body, simultaneously controlling the growth of each part. (Image courtesy of David Van Vactor)
Theory once held that the axons grow like a ship laying the transatlantic cable: the growth of the axon's microtubule core simply follows the trolling of the actin-rich tip. But new HMS research shows that the actin is only part of the response to environmental cues, while the important steering is done by enzymes in the middle of the growth cone, where actin and microtubules mesh. These enzymes pick up signals from receptor proteins on the growth cone's surface and then direct both the crawling motion of the actin and the end growth of the microtubule line.
The researchers, led by associate professor of cell biology David Van Vactor and postdoctoral research fellows Haeryun Lee and Ulrike Engel, have found a first example of such a central enzyme: the Abelson tyrosine kinase (Abl). Previous research from Van Vactor's lab had shown that in the developing nervous system of Drosophila, the receptor protein Roundabout relies on Abl when it detects the repellent protein Slit. Then Abl activates another protein that hinders actin growth. The HMS team's newest finding is that Abl simultaneously activates a microtubule-hindering protein, Orbit/MAST, as well as an analog to Orbit/MAST in Xenopus frogs, dubbed CLASP.
In their paper, published in the June 24 Neuron, the researchers write that there are probably numerous other proteins that Abl works through, and many other enzymes that function much like Abl.
Genetic Variation Among People May Be Ten Times Higher than Previously Thought
Researchers have been combing the human genome for isolated nucleotide changes--and for good reason. Single nucleotide polymorphisms (SNPs) often occur in regions of the chromosomes associated with certain diseases and, when captured, could provide clues as to what causes people to develop these illnesses. But in their rush to track down SNPs, scientists may have missed a larger quarry. It now appears that human chromosomes exhibit vast patches of variation--massive insertions, duplications, and deletions."There is an enormous magnitude of variation beyond what was previously known," said Charles Lee, HMS assistant professor of pathology at Brigham and Women's Hospital. Lee, along with A. John Iafrate, clinical fellow in pathology, and colleagues, compared the genomes of 55 unrelated people using a relatively new method, array-based comparative genomic hybridization (array CGH). They found duplications and deletions resulting in varying numbers of gene copies at 255 loci. These large-scale copy-number variations (LCVs) were typically hundreds of thousands of bases long. They were also quite common. Healthy individuals exhibited an average of 12 detectable LCVs, the most widespread being found in every two to three people scanned. The findings appear in the September issue of Nature Genetics. The data on which the paper is based appears at http://projects.tcag.ca/variation.
Until recently, humans were thought to differ genetically from one another by about a tenth of a percent of their DNA. Considering the number of LCVs and their size, the researchers believe that figure may be much larger. "If you take into account 255 loci in the human genome and multiply that by the average size of an LCV, 300 kilobases, that could represent as much as one percent of the human genome, a tenfold increase in variation over what was previously thought to exist," said Lee.
Another team of researchers, using a different method for scanning the genome, has come up with similar findings. Though some of the LCVs identified by Iafrate, Lee, and colleagues occur in noncoding regions of the genome, about half overlap with known genes--and that could make them as valuable as SNPs in diagnosing and possibly preventing illness.
Compound Fends Off Stroke Damage
In ATP's race to keep cells functioning, creatine is a pit crew of molecules that loads this molecular complex with phosphate-bond energy. Athletes have long taken advantage of creatine supplements to add a little extra fuel to skeletal muscle during workouts. Now, Brigham and Women's Hospital researchers have shown that creatine supplements can help keep neurons running without sustaining as much damage during a stroke. In the process, the team has offered some of the first direct evidence that preserving the ATP energy level of a cell is linked to forestalling the release of cytochrome c and the ensuing caspase cascade that leads to cell death.Led by surgery research fellow Shan Zhu and associate professor of surgery Robert Friedlander, the team fed mice a diet that was two percent creatine for four weeks. They then blocked the rodents' middle cerebral artery for two hours. The researchers found that compared with mice on a normal diet, the ischemic brain tissue of creatine-fed mice suffered 56 percent less infarction, held significantly less caspase-3 and cytochrome c, and lost half as much ATP.
It is not known how ischemia induces the caspase cascade, but scientists believe it results from stress put on the mitochondria, which are responsible for releasing cytochrome c. Preserving the level of ATP in a cell may help alleviate this stress, delaying the cytochrome's release.
Exactly how creatine maintains its concentration in cells is also a mystery. The creatine from supplementation does not significantly build up in brain tissue; however, during ischemia, the tissue retains 14 percent more creatine than that of normal mice. In addition, mice on a supplemented diet for only a week did not receive any of the benefits seen from a four-week-long diet.
In their paper, published in the June 30 Journal of Neuroscience, the team proposes that creatine, commonly used as a sports supplement, could someday be taken as a preventive by those with a high risk of stroke.
Novel Drug Design Approach Aims at Resistant Bacteria
At the 228th national meeting of the American Chemical Society, held the week of Aug. 23 in Philadelphia, HMS researchers led by Christopher T. Walsh reported a way to produce novel aminocoumarins, antibiotics that can fight drug-resistant bacteria.Currently, doctors have precious few weapons against bacterial strains like methicillin-resistant Staphylococcus aureus (MRSA). Though some of these super bugs are sensitive to aminocoumarins, there's a catch. Low solubility, poor absorption and distribution, and the inability to penetrate the bacterial cell wall, make these compounds less than ideal antibiotics.
Walsh, the Hamilton Kuhn professor of biological chemistry and molecular pharmacology, and colleagues described a method that can be used to generate potentially hundreds of aminocoumarin variants. "This approach allows the controlled variation of all parts of the aminocoumarin scaffold in the search to create antibiotics with tailored and improved properties," Walsh said.
In an ironic twist, the method exploits bacterial enzymes. Caren Freel Meyers, a research fellow in Walsh's lab, used an alphabet soup of proteins from Streptomyces to make an enzymatic production line that adds, stepwise, different chemical moieties to the backbone of coumermycin A1, a member of the aminocoumarin family of antibiotics.
Starting with this coumermycin scaffold, Freel Meyers used the enzyme CouL to add one or two amino groups, then CouM to add a sugar component called L-noviose. The enzyme CouP was found to add methyl groups to the CouM products, and NovN was used to add one or two carbamoyl moieties to methylated CouP product variants. By playing mix and match with enzymes and CouL substrates that make up the coumermycin A1 backbone, multiple designs can be produced. Freel Meyers has generated nine coumermycin variants, and three have been produced in sufficient quantity for detailed analysis.
--Tom Fagan