Sleep Medicine:
Extended Shifts for Residents Called Risky for Patients

The State of HSPH:
Bloom Reviews Faculty Research, Welcomes Allston Planning Role

Pathology:
Neurons Use Noodle When Motoring

Neurobiology:
Technique Begins to Decode Spiny Signaling in Brain

Graduate Education:
PhD Programs Added in Systems Biology, Chemical Biology

Protein Tied to Opportunistic Bacterium's Adaptability

Gene Expression Profile Predicts Survival in Ovarian Cancer

Birth of Motor Neurons Connected to Spinal Cord Induced in Adult Brain

Proceedings of the HMS Faculty Council

Five from HMS and HSPH Appointed to IOM

Grants Advance Research on Childhood Brain Tumors

Talking to the Public: How Can Media Coverage of Medicine Be Improved?

Med Ed Day Marks Progress of Curriculum Reform

Front Page

Protein Tied to Opportunistic Bacterium's Adaptability

A strain of Pseudomonas aeruginosa lacking the gene for RetS (right) shows stronger adherence to itself (rod-shaped cells) and to model mammalian cells (large bodies) than does a wild-type strain (left). The increased adherence reflects the ability of RetS mutants to form the extensive biofilms usually seen only in chronic infection. (Image courtesy of A. Goodman)

In order to investigate how P. aeruginosa is able to adapt so well to its environment, Goodman examined the genome sequence and selectively mutated 39 genes that resemble known environmental sensors. "We suspected that some of these genes might be required for biofilm formation," he said, "and that when we knocked them out, we would see a loss of the ability to maintain a chronic infection." The opposite proved true for RetS. Mutants lacking this protein displayed increased biofilm formation. They could not initiate an acute infection and were unable to activate the type III secretion system. When mice were inoculated with the RetS mutant, the bacteria were unable to colonize the animals' lungs, indicating that their ability to launch an acute infection was indeed compromised.

RetS is predicted to be a complex protein containing a kinase domain that acts as a sensor of environmental conditions and two regulator domains that could modulate intracellular signaling pathways. To determine which pathway RetS might control, Goodman conducted both microarray and genetic experiments, which showed that multiple virulence factors require RetS for their activation. Additionally, the researchers found that RetS likely functions by regulating the GacS/GacA/rsmZ pathway, known to be involved in controlling virulence.

"Understanding how virulence factors are controlled is a good way to find targets for drug design," Goodman said.

--Jillian Lokere

Gene Expression Profile Predicts Survival in Ovarian Cancer

As is typical in ovarian cancer, most of the 68 women in the study were diagnosed with advanced disease that had spread to the upper abdomen. In another heartbreaking but common feature of the disease, many women, including those with the most virulent form, had a complete remission after the first round of the conventional platinum/ taxane chemotherapy. Then the cancer returned.

Clinical features, such as tumor grade and amount of disease remaining after the initial surgery, are only rough guides to prognosis, said senior author Stephen Cannistra, HMS associate professor of medicine at Beth Israel Deaconess Medical Center. In contrast, this study identified a gene expression pattern in tumors that was associated with an approximately 70 percent chance of surviving for five or more years.

"For physicians who treat ovarian cancer, that kind of prognostic power is absolutely amazing," Cannistra said.

The researchers began with tissue and outcomes data from patients at BID and Memorial Sloan-Kettering Cancer Center. They examined half of the samples for key differences in gene expression in women at the extremes of overall survival. After refining the gene expression profile in the test population, they used the profile to predict survival in the other half of the samples. The result is the 115-gene signature they call the Ovarian Cancer Prognostic Profile (OCPP). The profile includes both tumor tissue and the surrounding stroma that it invades.

The OCPP needs to be replicated in prospective studies, said Cannistra. Even then, its best initial use may be as a research tool to probe the molecular underpinnings of disease and to select women with the most unfavorable profiles for clinical trials of new therapies, he said.

Study co-authors include first author Dimitrios Spentzos, HMS instructor in medicine at BID.

--Carol Cruzan Morton

Birth of Motor Neurons Connected to Spinal Cord Induced in Adult Brain

Previous work in the Macklis lab has shown that specifically killing certain cerebral cortex neurons prompts endogenous neural precursors to produce replacements in adult mice. It was not known, however, if this approach could induce the birth of corticospinal motor neurons, which connect from the brain to the spinal cord.

To find out, Chen injected chemically conjugated nanospheres into the spinal cords of mice, where they were taken up by the projections of corticospinal motor neurons. When exposed to long-wavelength light, the chemical caused the neurons to undergo apoptosis. Chen found that this triggered the birth of immature neurons, which migrated to the damaged region and matured into corticospinal motor neurons. "Some of these survived for over one year," Chen said.

The researchers probed further. "Our second question was, could a newly recruited neuron send an axon all the way to the spinal cord, which in an adult mouse is about 15 millimeters," said Macklis.

The answer was yes. Using cellular markers and fluorescent dyes, Chen saw that about 10 percent of the newly recruited neurons were able to make projections to the spinal cord. While this demonstrated proof of principle, approximately 90 percent of the new neurons eventually died, and the remainder was not enough to replace those that had degenerated.

Why did so many of the new neurons die? The answer probably lies in timing. "It took about four months for most of the neurons to send their axons down the spinal cord," said Macklis, "because the distance in an adult is 10-fold greater than it is early in development." Neurons require active connections to escape pro-apoptotic signals, so the delay likely caused most of the new neurons to self-destruct.

The next step is to improve the system to make it more clinically relevant. "Our goal is to understand the molecular programs that we could use to induce neurogenesis without first killing cells," Macklis said. "We would also like to find ways to recruit more neurons, to speed their axonal elongation to reach targets sooner, and to support the newborn neurons before they get to their target."

--Jillian Lokere