Stem Cells Discovered in Fruit Fly Gut, Tied to Notch Pathway

Adult stem cells are critical to maintaining organ systems, and when their ability to divide and differentiate is disrupted, certain cancers may result. Craig Micchelli, HMS research fellow in genetics and a member of the Harvard Stem Cell Institute, and Norbert Perrimon, Howard Hughes investigator and an HMS professor of genetics, present evidence in the Dec. 7 online edition of Nature that stem cells reside in the adult Drosophila midgut epithelium. They also illuminate the cell signaling pathway that tells each stem cell daughter whether to differentiate or to become a new stem cell.

Image courtesy of Craig Micchelli

This confocal micrograph of the adult Drosophila gut epithelium (red) shows the stem cells within this tissue (green).

Micchelli and Perrimon showed there are stem cells in the midgut epithelium by labeling cells with a fluorescent tag that is passed down to descendant cells. The tag revealed that some of the individually labeled cells gave rise to differentiated daughter cells of various types, as well as to more stem cells.

The investigators next sought to identify the stem cells. A systematic examination of the cells’ gene expression turned up escargot, a gene known to be present in other types of stem cell.

The researchers also tagged cells with a monoclonal antibody that was known to mark only proliferating cells. Cells tagged with the antibody also contained escargot, providing additional evidence that these cells were stem cells.

Micchelli and Perrimon next investigated the molecular mechanisms that determine whether a stem cell will divide to produce another stem cell or a differentiated daughter cell. They discovered that when a stem cell was dividing, only one of the daughter cells responded to the notch signaling pathway. This is important, said Micchelli, because notch signaling is known to promote differentiation. “We were quite intrigued to see that only one of the daughters is responsive to the notch pathway.” This observation suggested that the notch pathway may play an important role in regulating the balance between proliferation and differentiation in stem cells.

Then the investigators tested this hypothesis. “When we reduced notch signaling in stem cells, so that neither of the daughter cells could respond to notch signaling, we observed an increase in the number of stem cells,” said Micchelli. “However, activating the notch pathway in stem cells appeared to promote the formation of differentiated cells.

“We’re hopeful that understanding the molecular basis of stem cell behavior may lead to insights into diseases such as familial adenomatous polyposis, sporadic colorectal cancer, and intestinal adenomas,” Micchelli said.

—David Holzman

Function of “Unicorn” Whale’s Eight-foot Tooth Discovered

HSDM researcher Martin Nweeia has answered a marine science question that eluded the scientific community for hundreds of years: why does the narwhal, or “unicorn” whale, have an eight-foot-long tooth emerging from its head and what is its function? A clinical instructor in restorative dentistry and biomaterials sciences, Nweeia presented his conclusions at the 16th Biennial Conference on the Biology of Marine Mammals in San Diego on Dec. 13.

The narwhal has a tooth, or tusk, which emerges from the left side of the upper jaw and is an evolutionary mystery that defies many of the known principles of mammalian teeth. The tooth’s distinctive spiral, the degree of its asymmetry to the left side, and its odd distribution among most males and some females are all unique characteristics. The narwhal is usually 13 to 15 feet long and weighs between 2,200 and 3,500 pounds. Its natural habitat is the Atlantic portion of the Arctic Ocean, concentrating in the Canadian High Arctic: Baffin Bay, Davis Strait, and northern Hudson Bay. It also appears in fewer numbers in the Greenland Sea, extending from Svalbard to Severnaya Zemlya off the coast of Russia.

Nweeia has discovered that the narwhal’s tooth has hydrodynamic sensor capabilities. Ten million tiny nerve connections tunnel their way from the central nerve of the narwhal tusk to its outer surface. Though seemingly hard and rigid, the tusk is like a membrane with an extremely sensitive surface, capable of detecting changes in water temperature, pressure, and particle gradients. Because these whales can recognize particle gradients in water, they can discern the salinity of the water, which could help them survive in their Arctic ice environment. It also enables the whales to detect water particles characteristic of the fish that constitute their diet.

“Why would a tusk break the rules of normal development by expressing millions of sensory pathways that connect its nervous system to the frigid arctic environment?” said Nweeia. “Such a finding is startling and, indeed, surprised all of us who discovered it.” He collaborated on this project with Frederick Eichmiller, director of the Paffenbarger Research Center at the National Institute of Standards and Technology, and James Mead, curator of Marine Mammals at the National Museum of Natural History of the Smithsonian Institution.

—Leah Gourley

Not-for-profit Medicare Health Plans Outshine For-profits in Selected Measures

Managed care health plans that are not-for-profit provide better quality of care to Medicare beneficiaries than do those that are for-profit, according to a study by Eric Schneider, assistant professor in the Department of Health Policy and Management at HSPH, and colleagues there and at HMS. The research is published in the December 2005 issue of The American Journal of Medicine.

“These results are particularly important for two reasons,” the researchers write. “First, since the late 1990s, the majority of health plans that have enrolled Medicare beneficiaries have been for-profit. Second, the measures we studied are based on widely accepted standards of care for the clinical services they assess. There is a high degree of consensus that these clinical services can reduce morbidity and mortality if beneficiaries receive them.”

Using data from the Medicare Health Plan Employer Data and Information Set (HEDIS), the study compared outcomes among 303,718 beneficiaries from 294 managed care health plans under Medicare Advantage (formerly Medicare+Choice), for each of four clinical services: breast cancer screening, diabetic eye examination, beta-blocker medication following myocardial infarction, and follow-up after hospitalization for mental illness. Quality of care among for-profits was lower for all services, respectively by 7.3 percent, 14.1 percent, 12.1 percent, and 18.3 percent (although, due to sample size, the difference was insignificant for beta-blocker medication following MI.)

Past studies comparing for-profits and not-for-profits had come to conflicting results. But in 1997, reporting HEDIS data to the Centers for Medicare and Medicaid Services became mandatory for Medicare providers. This offered “the first opportunity to take advantage of the standardized quality measures in a mandatory program,” said Schneider.

Besides eliminating the possibility of bias due to voluntary reporting, the new study takes advantage of data that enables adjustment for both individual characteristics and enrollment-related selection effects, verifying that “lower quality of care in for-profit health plans was not an artifact of sociodemographic differences,” the researchers write.

“We know that some areas of the country, for reasons not entirely understood, are associated with lower quality of care in the measures in the study,” Schneider said, so it was possible that any inferiority of for-profit plans might result from their being more likely to operate in those areas. “But when we took that into account,” he explained, “it didn’t change the central finding.”

Another hypothesis regarding the possible superiority of care at not-for-profits had been that for-profits might be more likely to restrict high-cost surgical procedures than not-for-profits. Yet the researchers reported last year in The New England Journal of Medicine that this was not occurring.

Schneider speculates that a greater focus on short-term profits among the for-profit plans due to the exigencies of the stock market might account for the new results. Despite the findings, the authors recommend against barring for-profits from participating in Medicare, suggesting that these plans might have better quality of care than fee-for-service plans, which cover more than 80 percent of Medicare beneficiaries, and because a blanket prohibition would remove even the high-performing for-profits.

—David Holzman

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