April 22, 2005
Immunology
Body Builds Defense
Against Pneumococcus
Without Antibodies
At the Podium
Race Complicates Views on Genes And Medicine
Neurosurgery
Aggressive Surgery for Low-grade Brain Tumor May Lengthen Life
Medical Education
Website Opened to Support Cross-cultural Care
Entire Fruit Fly Genome Plumbed for Pathway Participants
Molecular Teams Decide Nerve Cell Fates
Blue Light Puts Red Gums in the Pink
Grant to Improve Managed Care Treatment of Drug Abuse
New Faculty Appointments to Full Professor
Plasmid Repository Supports Research in Genomics
Longwood Symphony Gives Benefit for Homeless Patients
Innovator Award Goes to HSPH Cancer Researcher
Honors and Advances
News Brief: AMA Foundation 2005 Leadership Awards
Name of Countway’s Rare Books Department Is History
Nine Students from LMA Selected as Schweitzer Fellows
HST Student Research Reaches for the Stars
Entire Fruit Fly Genome Plumbed for Pathway Participants
HMS professor of genetics Norbert Perrimon and colleagues have completed the first survey of the entire Drosophila genome for genes involved in a specific signaling cascade. Problems in this pathway, called Wnt, are implicated in breast, liver, skin, and colon cancers and Alzheimer’s disease. Their screening technique is applicable to other signaling pathways, as well. The results of the study, whose first author is HMS research fellow Ramanuj DasGupta, appeared online April 7 in Science.
| The results suggest that the majority of hits in the Drosophila RNAi screen will be relevant to vertebrates. |
Perrimon is known as an innovator in applying RNAi in high-throughput screening techniques. Working in Perrimon’s lab, DasGupta spent months developing the screen to demonstrate whether the Wnt pathway had been knocked down or stimulated in a culture of Drosophila cells. Once the screen was perfected, it only took a few weeks to check each of the 22,000 genes in the Drosophila library. He found 238, of which fewer than 30 had been previously implicated in the pathway.
“When you get results like this, you’re a little overwhelmed. What you have to do next is prioritize,” DasGupta said. The most important discoveries are genes that can be mapped to known counterparts in humans. After searching human genome databases for the most likely matches, DasGupta collaborated with University of Washington researchers to test suspected vertebrate Wnt genes in human cell culture and in zebrafish embryos. (Broad initial screening of entire mammalian genomes with similar RNAi technology is prohibitively expensive since antiviral defenses destroy the longer RNA strands that can be used to knock down the genes in lower organisms.)
The results suggest that the majority of hits in the Drosophila RNAi screen will be relevant to vertebrates, and the team has released the entire list of candidates. “We want clinical people to read this,” DasGupta said, emphasizing that 18 percent of the candidate genes can be matched to disease-related human genes.
Perrimon said future inquiry will include a similar overview of genes
involved in the Hedgehog signaling pathway, working toward an analysis
of both shared
and unique cellular machinery for various
signaling mechanisms.
Molecular Teams Decide Nerve Cell Fates
A recent study by researchers from HMS and other institutions describes how regulators team up to trigger the expression of multiple subtype-specific characteristics in single neurons of Drosophila melanogaster. Lead author Douglas Allan, HMS research fellow in neurology at Children’s Hospital Boston, and colleagues report the findings in the March issue of Neuron.
Allan collaborated with Massachusetts General Hospital research fellow Susan St. Pierre and a team at Washington University in St. Louis. His work on the study was done in the lab of HMS assistant professor Stefan Thor, who is now at Linkoping University in Sweden.
| “There are fewer transcription factors than there are cell types—that suggests combinatorial coding.” |
So he set out to determine how neurons decide on the unique combination of characteristics to express in their final, fully differentiated state. Allan examined a population of 90 neurons (out of Drosophila’s 20,000 total) that express the apterous gene, looking at how the sqz, ap, and dimm regulatory genes and the BMP signaling pathway control axon pathfinding and the neuropeptide expression and processing characteristic of these particular cells.
The team found that different combinations of these four factors specify unique characteristics expressed by different neurons, and biochemical experiments suggested that the factors could physically interact, providing a physical basis for the combinatorial code. But in these same cells, sqz, ap, and dimm also dictated other aspects of cell differentiation, independent of the other molecules in the code. Allan proposes that it may be common to see a single master regulator, such as dimm, independently trigger generic characteristics in a cellular lineage and then also show up as one element of a combinatorial code that determines subtype-specific characteristics appropriate to that cell type.
This research was done in Drosophila because similar work in vertebrates runs into serious challenges. Ap-family mutants in vertebrates usually lose the relevant tissue due to directed cell death, making it difficult to evaluate the roles of such regulators in neuronal differentiation. But in the tiny brains of fruit flies, single cells can be identified in the majority of mutants and the consequences of their disruption analyzed. Allan sees these factors as a real advantage of simpler animals. “In Drosophila systems, we’re learning lessons that can be applied to mammals, where you can’t so easily look at single neurons.”
Blue Light Puts Red Gums in the Pink
Researchers at the Forsyth Institute report that blue light can selectively kill pathogenic bacteria that cause periodontal disease.
If clinical studies show that it works as hoped, blue light could be used prophylactically to prevent or control the disorder. The researchers envision a flexible handheld device about the size of a toothbrush.
| “This form of treatment would offer many advantages. It is painless, rapid, and devoid of drug toxicity.” |
The line of research advances an emerging ecological principle for treating serious gum disease, said lead author Nikolaos Soukos, HMS instructor in dermatology at Massachusetts General Hospital and director of the Forsyth Laboratory of Applied Molecular Photomedicine.
In a healthy mouth, dental plaque is composed of about 500 to 600 different bacteria living in harmony. “The problem starts when some of the potentially pathogenic bacteria take over, multiply, and become more aggressive,” said Soukos, a dentist and oral pathologist. “We want to selectively target the bad guys, so we can reintroduce a balance.” In contrast, current treatments focus on destroying all the bacteria lurking in diseased gums.
The project started with an observation by senior author Max Goodson, HSDM associate clinical professor of periodontology and director of clinical research at Forsyth, that a clinical trial of a tooth whitening process appeared to decrease inflammation of the gums. “It was a considerable surprise,” said Goodson, who had anticipated that the treatment—pairing blue light with concentrated peroxide gel on the teeth—might irritate the gums.
In the one-hour whitening procedure, the gums are carefully shaded, but Goodson and Soukos speculated that some of the light reached the gums and killed photosensitive bacteria there.
To test their idea, the researchers zapped laboratory strains of four of the nastiest oral bacteria with a lower-energy dose of blue light. One minute’s glow killed most of the microorganisms, including Porphyromonas gingivalis, which has been implicated in both gum disease and associated heart attacks. These particular bacteria naturally contain high levels of porphyrins, a family of compounds that generate toxic oxygen species, such as singlet oxygen and free radicals, when exposed to light.
Then the researchers collected dental plaque from people’s teeth. The blue light preferentially blazed through the disease-causing bacteria rich in porphyrins, compared to the 36 other species they analyzed in the samples. At the March meeting of the International Association for Dental Research, Goodson reported encouraging data from preliminary pilot tests in 11 people so far.
“Most people are skeptical that it is going to have a major effect,” Goodson said. “That’s a reasonable thing to be at this point. We’ve shown there is real promise, but we have a long way to go before we have a convincing case.”