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RESEARCH BRIEFS
New Twist Reported in Blocking Plaque-forming ProteinsCorkscrew-shaped molecules appear to block cells from making the plaque-forming protein pieces implicated in Alzheimer's disease, say the researchers who designed them.
Small spiral molecules designed to mimic the shape of amyloid-beta precursor protein (APP) appear to work at the first stage of the interaction with gamma-secretase by blocking APP's docking site on the protease surface. (Image courtesy of Michael Wolfe) The small spirals are the first of a new class of potential drug candidate for Alzheimer's, as well as important new scientific tools for probing the underlying mechanisms of Alzheimer's and other diseases, according to a paper published in the Sept. 6 advance online edition of the Journal of the American Chemical Society. In some cases of inherited, early-onset Alzheimer's disease, too many of the amyloid-beta protein pieces cut loose from the cell accumulate as the aggregates and plaques that many believe cause neurodegeneration. Amyloid-beta is implicated in the etiology of sporadic, late-onset forms of the disease, as well. The protein pieces come from amyloid-beta precursor protein (APP), which is first clipped by the protease beta-secretase and then further trimmed by gamma-secretase, a protease in cell membranes whose final cut produces the potentially dangerous protein pieces associated with Alzheimer's. In this study, the helix-shaped molecules blocked APP from sticking to gamma-secretase. This spring, working in yeast, fruit fly cells, and mammalian cells, three independent research teams, including Michael Wolfe and his colleagues, identified the close-knit gang of four key proteins that compose gamma-secretase (See Focus, June 6, 2003). "It's a ridiculously complicated protease," said Wolfe, senior author on the current paper and an HMS associate professor of neurology at Brigham and Women's Hospital. "Like other proteases, when it gets a protein in its grip, it uses water like a knife. The unusual thing is that gamma-secretase cuts with water in the water-hating environment of the cell membrane." Surprisingly, one of the most potent potential blocking compounds tested was a left-handed spiral molecule (with D-amino acids). Proteins in the body usually contain right-handed spirals (with L-amino acids). The powerful "peptide 17" blocked about half the test cells' amyloid-beta production at very low concentrations. Some hereditary, early-onset forms of Alzheimer's disease involve mutations in gamma-secretase. Most cases of late-onset Alzheimer's disease probably have nothing to do with a defect in gamma-secretase, but targeting amyloid-beta production is still considered a high priority for drug development for pharmaceutical companies. The work was led by postdoctoral fellow Chittaranjan Das and conducted in collaboration with the Massachusetts General Hospital lab of Bradley Hyman, the John B. Penney, Jr. professor of neurology at HMS. Wolfe anticipates the helical molecules may be even more important as research tools to understand how gamma-secretase works and to inhibit other proteases of its kind. For example, other types of helical peptides could block the docking site for a protease that governs an early step in turning on genes that make cholesterol in the body. Spiral molecules might also serve as bait to fish out other undiscovered proteases of this type.
Novel Tumor Suppressor Shows Unusual PowersTumor suppressors enjoy celebrity status in molecular biology--and for good reason. As guardians of the genome, their job is to make sure the DNA is in perfect shape before a cell starts to divide. Without them, an orderly dividing, healthy cell could give rise to a pile of madly replicating tumor cells.So it is not surprising that the discovery of a new tumor suppressor gene by Craig Bassing, Fred Alt, and their colleagues, has molecular biologists buzzing. Their Aug. 8 Cell paper, which appeared back-to-back with another paper on H2AX by researchers at the National Cancer Institute, was greeted by widespread commentary in journals such as Science, Nature, and Lancet. What made the publication especially newsworthy is the power of the gene H2AX. Normally, both copies of a tumor suppressor gene must be lost for a cell to make the descent into cancer. But Bassing, HMS instructor in pediatrics; Alt; and colleagues found that cancer-primed mice lacking a single copy of H2AX developed tumors at nearly the same rate as those in which both genes were lost. "This is a very novel class of tumor suppressor," said Alt, the Charles A. Janeway professor of pediatrics. The news does not come entirely out of the blue. Researchers had considered H2AX a promising candidate even though it differs from many tumor suppressors in being a chromosone-structuring histone rather than an enzyme. It was known to interact with other tumor suppressors. In fact, ATM, a master regulator of DNA repair, was known to mark sites of DNA damage by placing a phosphate group on H2AX. In addition to serving as a signal for DNA damage, Bassing, Alt, and colleagues thought the molecule might actually be assisting in repair. Bassing generated a series of knockout mice to test the hypothesis. The first set of mutants, lacking two copies of H2AX, showed a somewhat high incidence of lymphoma, but nothing dramatic. Knowing that many cancers require two mutational hits, Bassing removed both H2AX and tumor suppressor p53. The results were stunning. Mice lacking just p53 die of cancer 6 to 8 months after birth. The double-knockouts were barely 10 to 12 weeks old when they succumbed, and they died from a wide variety of blood and solid tumors. But the greatest surprise was that p53-deficient mice lacking only one copy of H2AX died just as quickly, and from almost the same cancers. Alt believes the reason one copy makes such a dent is that H2AX is a relatively sparsely distributed histone. Two copies of the gene produce enough protein to decorate only 10 to 15 percent of DNA. One copy would produce even less, which is obviously not enough to carry out its essential functions. "For an enzyme, this might be difficult to understand, but for a structural protein it is not hard to envision," he said. What is more, H2AX may be working with p53 in a coordinated fashion. "If you get rid of either one, it is not so bad," he said. "But when you lose both, you cannot repair damage and do not recognize cells with damage. All hell breaks loose." This scenario could play out in humans as well as mice. It turns out, H2AX lies in a cancer hotspot on human chromosome 11. "H2AX maps to a region that is defective in a very large proportion of human cancers," said Alt. In fact, researchers have been scouring this region for tumor suppressors, but they may have been stymied by an unwarranted assumption--that you need to lose two copies of a gene to get cancer. "No one has considered the possibility of losing just one copy," he said. "This is one of the most exciting things we have found in a very long time." --Misia Landau
Physicians Writing Fewer Antibiotic PrescriptionsWith antibiotic resistance reaching critical proportions, U.S. public and private health agencies have waged an intensive campaign over the past five years to reduce overprescription of antibiotics.These efforts may be paying off, a study led by HMS researchers suggests. Jonathan Finkelstein, HMS assistant professor of ambulatory care and prevention and of pediatrics, collaborated with researchers from health plans in the national HMO Research Network to analyze data on physician visits and prescriptions for 225,000 children, aged three months to 18 years, enrolled in nine health insurance plans from 1996 to 2000. During this period, they found, antibiotic prescriptions declined 24 percent for children three months to three years of age, 25 percent for children three to six years old, and 16 percent for those six to 18 years old. A decrease in prescriptions for otitis media (middle ear infection) accounted for 59 percent of the total decrease, the researchers found. This drop was due largely to a decline in diagnoses of otitis media by physicians during the study period, following a rapid increase in such diagnoses in the 1980s. The investigators believe physicians have become more conservative in diagnosing these ear infections. Similarly, for other conditions--including pharyngitis, sinusitis, and bronchitis--the decline in antibiotic use was driven more by a decline in the number of diagnoses than a decreasing proportion of diagnosed cases being treated with antibiotics. "Attention by public health and professional organizations and the news media to antibiotic resistance may have contributed to changes in diagnostic thresholds, resulting in more judicious prescribing," the authors write. Finkelstein is associate director of the Center for Child Health Care Studies in the Department of Ambulatory Care and Prevention of HMS and Harvard Pilgrim Health Care. Other department faculty--Richard Platt, professor and chair, and Kenneth Kleinman, assistant professor--are co-authors of the paper, which appears in the September Pediatrics. --Tom Reynolds
U.S. Health Costs Triple Those of CanadaDespite managed care's efforts to streamline U.S. health care and cut expenses, health administration costs reached $1,059 per capita in the United States in 1999--more than three times as high as Canada's $307 (U.S.) per capita.The calculation was made by Cambridge Hospital and HMS researchers David Himmelstein and Steffie Woolhandler, both associate professors of medicine, in collaboration with Terry Campbell of the Canadian Institute for Health Information. The researchers analyzed published data, physician surveys, employment data, and cost reports from hospitals, nursing homes, and home care agencies. They estimate that 31 percent of U.S. health care expenditures went to administration compared with 16.7 in Canada, and they tag 1999 health administration costs in the United States at $294.3 billion. They also found that the proportion of administrative and clerical personnel in the U.S. health care work force rose from 18.2 percent in 1969 to 27.3 percent in 1999. In Canada, this proportion grew more modestly, from 16 percent in 1971 to 19.1 percent in 1996. "A large sum might be saved in the United States if administrative costs could be trimmed by implementing a Canadian-style health care system," say the authors. The findings appear in the Aug. 21 New England Journal of Medicine. In the Aug. 13 JAMA, the Physicians' Working Group for Single-Payer National Health Insurance outlines its proposal for such a system and describes the benefits that could accrue if implemented. Woolhandler, Himmelstein, and Marcia Angell, senior lecturer in the Department of Social Medicine, are among the authors of the proposal. --Tom Reynolds |
