Cell Biology:
Live-cell Studies Pick Up Pattern in Vesicle Traffic
Radiology:
Imaging Method Reveals Which Mice Develop Type 1 Diabetes
Endocrinology:
Fat Hormone Revives Reproductive Systems of Lean Women
Systems Biology
Systems Biology, the New Physiology, Marks First Year at HMS
Chemical Staples Turn Flimsy Peptide into Cancer Killer
Female Flies Join Food Fight
Time Zone Controls Limb Size
Images of Rotavirus Entry Show Bug the Exit as Childhood Killer
Contract Supports Research in Biodefense Proteomics
HSPH and Cyprus Establish International Initiative
HMS Welcomes Incoming Students
Stearns Appointed Associate Master of Castle
The Myrto Lefkopoulou Lectureship
Applications Wanted for Health Care Research
Longwood Symphony Season Opens
Honors and Advances
In Memoriam:
Leroy Vandam
Leonard Safon
Robert Moylan
Students Aid Families with Special-needs Children
Students Orient Themselves Toward Medicine
Chemical Staples Turn Flimsy Peptide into Cancer Killer
Cancer cells may now be their own worst enemy. Harvard researchers report in the Sept. 3 Science that they were able to make leukemia cells kill themselves by improving upon a naturally occurring molecule. Loren Walensky, HMS instructor in pediatrics at Children's Hospital Boston, is the lead author of the study in which he reconstructed a section of a protein that normally prompts cells to commit suicide and then used a hydrocarbon "staple" to chemically strengthen it. The modified molecule proved to be a finely honed weapon against leukemia cells.Howard Hughes investigator Stanley Korsmeyer, co-senior author and the Sidney Farber professor of pathology at HMS and Dana-Farber Cancer Institute, has long studied programmed cell death. Some cancer cells exploit the cell death pathway by overexpressing anti-apoptotic proteins, enabling them to nullify signals for self-destruction. Scientists have sought to target this apoptosis pathway with small molecule therapeutics for several years.
Walensky and Korsmeyer teamed up with co-senior author Gregory Verdine, a professor of chemistry at Harvard University, to take a different approach. "Rather than design a molecule from scratch, we strengthened something that we already knew was designed by evolution to work," said Walensky. Previous research had shown that the alpha-helical peptide BH3 can inhibit anti-death proteins and, in certain circumstances, directly activate pro-death proteins. The problem with the naturally occurring BH3 peptide is that it loses its shape when taken out of its parent protein. Without this conformation, BH3 is vulnerable to degradation and unable to penetrate cells to exert its effect. The solution was to replace several natural amino acids within BH3 with non-natural ones that could be bound together through a hydrocarbon linkage. "The beauty of the hydrocarbon linkage is that it is exquisitely stable. Just like a staple, it provides a rigid constraint to prevent things from coming apart," noted Walensky.
The improved molecule resisted decomposition, penetrated cells, and caused regression of leukemia xenografts in mice, allowing the treated mice to live longer than their untreated counterparts. "The alpha helix plays a critical role in many biological interactions, so the ability to chemically brace helical peptides from within has the potential to yield a whole new set of tools to study human disease," Walensky said.
--Jillian Lokere
Female Flies Join Food Fight
The harmless fruit fly may not be the most obvious choice for studies on aggression, but researchers in the lab of Edward Kravitz, the George Packer Berry professor of neurobiology at HMS, have been staging drosophila fights with clear winners and losers for several years.
Most recently, they put females in the ring (the surface of a food cup) and let them duke it out over an added dab of yeast paste, the dark chocolate of fruit fly food. Females display stereotypical patterns in their brawls as robust as their male counterparts, according to a new analysis of 52 fights conducted by postdoctoral fellows Steven Nilsen and Yick-Bun Chan. The study was published in the Aug. 17 Proceedings of the National Academy of Sciences.
When push comes to shove, females fight differently. Most notably, they favor a head butt (above; photo courtesy of Steve Nilsen) not seen in the male repertoire. Unlike fighting between males (see Lab Works), female fighting establishes no sustained hierarchical relationship.
The analyses of the female and male fighting behavior lays the groundwork for addressing the genetic basis of aggression in the brains of fruit flies.
--Carol Cruzan Morton
Time Zone Controls Limb Size
In the blobs of embryonic cells that eventually grow into a mouse, chicken, or a person, one protein, called Sonic hedgehog, plays a key role in directing each limb to its distinctive shape, especially the fine details in the paw, wing, and hand.Now, researchers have found a new dimension in the action of Sonic hedgehog and its homologues. They also have identified the built-in braking system that turns off the signaling protein when the job is done. In fact, one expanding band of cells helps explain both mechanisms, according to two papers from the lab of Cliff Tabin, HMS professor of genetics.
Early in development, a limb first emerges as a bud with a built-in organizational headquarters on one side, called the zone of polarizing activity. The zone churns out Sonic hedgehog. According to the prevailing theory, this protein then sculpts the digits by its dosage. One by one, beginning with the thumb or its equivalent, the digits grow farther and farther away from the zone and are exposed to less and less of the protein.
That's only part of the story, reports a paper in the Aug. 20 Cell, led by former postdoctoral fellow Brian Harfe, now on the faculty at the University of Florida College of Medicine. In mice, Harfe and his colleagues tracked zone cell descendants as they expanded and stopped making Sonic hedgehog. The researchers used a genetic tool known as recombinase fate mapping, which tracks stem cell descendants as they grow and specialize.
Their findings confirmed part of the classic model. Dwindling concentrations of hedgehog protein reached across the budding limb to shape the first two digits. Meanwhile, a growing band of former zone cells eventually formed part of the middle digit and all of the last two digits.
Sonic hedgehog, made in the zone, also directed the growth of the last few digits, but the level of exposure due to concentration became increasingly irrelevant. Surprisingly, the last two digits relied more on the length of time they are exposed to the protein.
"The idea that time matters is new," Tabin said.
In another paper in the July 16 Science, HMS graduate student Paul Scherz and his colleagues report that the same expanding band of former zone cells ultimately shut down Sonic hedgehog when a limb is fully formed in chicks.
To make hedgehog, the zone requires continued exposure to a second protein made from a nearby group of cells that are dependent, in turn, on hedgehog. This positive feedback loop involves several intermediary steps, including the production of Gremlin, a third protein made in cells on the rim of the zone. The expansion of the band of former zone cells pushes the margin of Gremlin-making cells out of the reach of hedgehog. When this limit is reached, Gremlin shuts down, interrupting the critical positive feedback loop, ultimately shutting down hedgehog.
The experiments were conducted in mice and chicks, but the new model of timing and growth control, as well as the signal to stop, likely applies to people, Tabin said.
--Carol Cruzan Morton
Images of Rotavirus Entry Show Bug the Exit As Childhood Killer
Among the hordes of pathogens trying to gain a foothold in day care centers all over the country, rotavirus is one of the more successful. Most toddlers have been infected with the diarrhea-causing bug by the time they are three. Though rotavirus can cause trouble--fever and vomiting as well as diarrhea--it rarely kills American children. Yet rotavirus-induced diarrhea claims the lives of about 440,000 children worldwide every year, most in developing countries. Part of the problem is that there are few viable vaccines against the bug.Researchers at Children's Hospital Boston have made a discovery that could be used to thwart the ubiquitous pathogen. Philip Dormitzer, HMS assistant professor of pediatrics, Steven Harrison, Howard Hughes investigator and HMS professor of biological chemistry and molecular pharmacology, and their colleagues have produced a set of high-resolution images that show how the virus enters cells. The findings appear in the Aug. 26 Nature.
Like most viral pathogens, rotavirus latches onto and enters host cells by means of surface proteins--in this case, a spike-forming protein, VP4. Dormitzer and his colleagues pared down VP4 to two components, the "head" and "body." After crystallizing these, they used X-ray diffraction to determine the components' three-dimensional molecular structures. When compared with electron microscopy images made by colleagues at Baylor College of Medicine, the crystal structures suggested that VP4 undergoes two consecutive shape changes. First, its molecules cluster to form a spike, the head of which binds the surface of the target cell. The spike then bends back into a folded-umbrella structure, perhaps allowing it to pierce the cell's membrane.
As it turns out, VP4's head and body contain many of the antigen targets that the immune system recognizes when it attacks the virus. The researchers are now collaborating with several other institutions to develop a vaccine.
--Misia Landau