Neurobiology:
Study Sees Brain in Process of Seeing
Cell Biology:
Finding NEMO: Latest Crohn’s Disease Clue
Public Health:
Prevention May Double the Effectiveness of Global HIV/AIDS Treatment
Genetics:
Do-It-Yourself DNA Poised to Remake Molecular Biology
Inflammation’s Other Face: Repairing Injury to the Brain
RNA–Protein Binding Makes Pathogen Irresistible
Down Syndrome Diagnosis Need Not Be Negative Experience for Mothers
Proceedings of the Harvard Medical School Faculty Council
Cambridge Health Alliance Gains HMS Affiliation
Fineberg Professorship Established to Advance Practice of Public Health
New Faculty Appointments to Full and Named Professorships
Connelly Named Assistant Dean for Faculty Affairs
News Brief
Ed Reform at a Critical, Malleable Phase
Inflammation’s Other Face: Repairing Injury to the Brain
In circumstances as different as multiple sclerosis and a bump on the head, doctors usually view inflammation of the brain as dangerous. But Samia Khoury, an HMS associate professor of neurology, and Jaime Imitola, an HMS postdoctoral fellow, found that damaged brain tissue releases a chemical lure to neural stem cells, which migrate to the site of injury and may be responsible for repair. Their research at the Center for Neurologic Diseases at Brigham and Women’s Hospital was conducted with colleagues from Bos-ton, California, and Korea and appeared in Proceedings of the National Academy of Sciences on Dec. 28.
Stemming Injury. The signaling molecule SDF-1 is secreted by cells near a brain injury, and received by a receptor, CXCR4, on human neural stem cells, which are prompted to migrate to the injury and mature into various types of brain cells.
In searching for inflammatory signals that might help them understand multiple sclerosis, Imitola and Khoury found the signaling molecule stromal derived factor 1 (SDF-1) among the hundreds of proteins expressed in inflamed brain tissue. SDF-1 is relatively straightforward to study because it couples to only one receptor, CXC chemokine receptor 4 (CXCR4). Most inflammatory signals are more complicated, with multiple chemokine messengers reaching multiple receptors in a tangled web of activation and response.
Khoury’s in vitro experiments showed that neural stem cells had active CXCR4 receptors and that they responded to SDF-1 by growing and migrating toward the source of the SDF-1 signal. Further experiments showed that causing a strokelike model injury, hypoxic ischemia, in the brains of mice brought injected human neural stem cells running to help. Khoury made the stem cells visible with a fluorescent label and saw them migrate, sometimes right across the brain, to implant themselves near the injury.
“The body uses the same pathways to do different things at different times,” Khoury explained. Researchers already knew that SDF-1 guides the migration of stem cells in embryonic brains. Since the current work has shown that the same signal and receptor are active in healing adult brains following inflammation, there is hope that this process can be influenced to favor repair.
Khoury’s basic research at the intersection of stem cells and inflammation could lead to insights into MS and other autoimmune diseases, as well as into the delicate mechanisms of brain self-repair. She is the codirector of Partners MS Center at BWH, and her next project uses an animal model of MS to identify signals that promote propagation and differentiation of neural stem cells.
—Tai Viinikka
RNA–Protein Binding Makes Pathogen Irresistible
The binding of a viral RNA and a viral protein transforms the 3' end of an invading pathogen into a structure irresistible to the viral replication machinery. New X-ray crystallography studies show that changed viral RNA “sticks out like a beacon compared with other RNAs in the cell,” according to team leader Lee Gehrke, HMS professor of health sciences and technology in the Harvard–MIT Division of Health Sciences and Technology and an HMS professor of microbiology and molecular genetics. He proposes that this distinctive, stable structure “allows replicase to jump right on.”
Gehrke and other biochemically oriented virologists knew that alfalfa mosaic virus (AMV) was not infectious until its genomic RNAs bound to viral protein, but the mechanism was unknown. Laura Guogas, a graduate student in Gehrke’s lab, used a structural approach to generate results that are “stunning and unexpected,” said James Hogle, the Edward S. Harkness professor of biological chemistry and molecular pharmacology. He and David Filman, an HMS lecturer on biological chemistry and molecular pharmacology, contributed to this study, which appears in the Dec. 17 Science.
Three-dimensional images show a floppy viral coat peptide contracting into an alpha helix, while a smooth strand of RNA dotted with hairpin structures develops what looks like a mountain turn on the Tour de France. The researchers attribute this kink to formation of additional links between the hairpins, another surprise from the three-dimensional structure.
“This project is a great example of the role a talented student can play in a collaboration between two labs with complementary interests and expertise,” said Hogle.The findings are especially interesting because AMV is a single-strand, positive-sense RNA flavivirus related to pathogens that cause emerging diseases such as dengue fever and West Nile. None of these flaviviruses have the polyA tail that ordinarily initiates translation of cellular RNAs into proteins. AMV substitutes the striking RNA–protein complex that Guogas identified; other family members no doubt have other solutions. Learning what these are could lead toward new vaccines and treatments.
—Patricia Thomas
Down Syndrome Diagnosis Need Not Be Negative Experience for Mothers
Mothers give doctors low marks on their delivery of a Down syndrome diagnosis. A study published in the January Pediatrics recommends a series of measures for improving a mother’s experience when told her child has this chromosomal abnormality. Brian Skotko, a student at HMS and at Harvard’s John F. Kennedy School of Government, surveyed 985 mothers in five states to identify the impact of the setting, timing, and manner of the delivery of the diagnosis. The study focuses on women who were unaware that their children would have the disorder when they were pregnant.
Skotko’s paper suggests ten changes in the way the Down syndrome diagnosis is delivered, aimed at improving the emotionally painful initial experiences that many mothers reported. Asked which improvements could be put into practice most easily and effectively, he replied that doctors need to know and convey current information about local Down syndrome support networks. Though these organizations help parents of children with the disorder, doctors frequently do not inform parents about them.
Skotko also asks doctors to reconsider starting the diagnosis delivery with, “I have some bad news for you.” He recommends, “Congratulations, you have a beautiful baby,” instead. As they further discuss the diagnosis, doctors should balance the negative aspects of the syndrome with the positives reported by parents, such as the loving nature of many children with Down syndrome and the ability many of them have to exceed society’s expectations.
“Mothers are just asking for that blend of facts and possibility,” Skotko said.
Finally, he urges doctors to make current information about Down syndrome available to parents. Even a bibliography, he argues, would be better than the out-of-date information frequently offered.
Skotko’s companion study, on the experiences of women whose children were diagnosed with Down syndrome prenatally, will be published in the American Journal of Obstetrics and Gynecology this spring. He says it, too, will challenge doctors to listen hard to mothers and change their practices accordingly.
—Tai Viinikka