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RESEARCH BRIEFS
Reproductive Cells Derived from Embryonic Stem CellsActive gametes can be derived from embryonic stem cells, according to a paper in the Jan. 8 Nature. The finding "will provide an invaluable model for studying gametogenesis and imprinting," said principal author George Daley, an HMS assistant professor who recently joined the Department of Biological Chemistry and Molecular Pharmacology and the faculty at Children's.
The gametes that George Daley and Niels Geijsen coaxed from embryonic stem cells promote cell division (shown here) when injected into oocytes, indicating that the gametes are biologically active. (Image courtesy of Niels Geijsen) Daley and first author Niels Geijsen, a principal investigator at the Center for Regenerative Medicine and Technology at Massachusetts General Hospital, together with colleagues at Harvard and MIT, reasoned that primordial germ cells might be found in embryoid bodies, partially differentiated structures that, like germ cells, are tightly associated with hematopoietic cell lineages. To test this hypothesis, Geijsen probed mouse embryoid cells for two marker proteins, SSEA1 and Oct4, expressed in both primordial germ cells and embryonic stem cells, but which are lost from the latter during differentiation. Sure enough, Geijsen found a small subset of cells in developing embryoid bodies that continued to express the two diagnostic marker proteins. The authors treated the cells with retinoic acid, which causes stem cells to differentiate, but causes germ cells to proliferate. Geijsen found that SSEA1 expression persisted in some of the embryoid cells, suggesting that the researchers had isolated primordial germ cells. During gametogenesis, imprinting--nature's way of switching off a specific selection of maternal or paternal genes--is reversed, usually by demethylation. The authors found that in the embryoid-derived germlike cells, normally imprinted genes, such as Igf2r, were demethylated. Also, as the cells matured in culture, they began to express proteins found in sperm mother cells, and some of the cells halved their chromosome number by meiosis. All these observations indicated that true gametes were being generated, but the icing on the cake came when the haploid cells were introduced into oocytes. About 50 percent of the injected cells divided to the two-cell stage, while about 20 percent went on to form blastocysts, showing the putative gametes were truly active. --Tom Fagan
Coffee Drinking Cuts Risk of Type 2 DiabetesDrinking six or more cups of caffeinated coffee a day reduced men's risk of developing type 2 diabetes by more than 50 percent and women's by nearly 30 percent, according to a study by researchers at HSPH and Brigham and Women's Hospital. Their findings appear in the Jan. 6 Annals of Internal Medicine.The study followed more than 125,000 participants in the ongoing Health Professionals Follow-up Study and the BWH-based Nurses Health Study who were free of diabetes, cancer, and cardiovascular disease. Subjects included 41,934 men and 84,276 women, who were tracked, respectively, from 1986 to 1998 and 1980 to 1998 via food frequency questionnaires that assessed coffee consumption. During the study, 1,333 new cases of type 2 diabetes were diagnosed in the men and 4,085 in the women, but the caffeinated-coffee drinkers were disproportionately absent from this group compared to non-coffee drinkers. Decaffeinated coffee also was beneficial, but its effect was weaker than regular coffee's. The researchers note that caffeine is known to raise blood sugar and increase energy expenditure in the short term, but its long-term effects are poorly understood. Both regular and decaffeinated coffee have antioxidants like chlorogenic acid and magnesium, which can improve sensitivity to insulin and may contribute to lowering risk of type 2 diabetes. "This is good news for coffee drinkers; however, it doesn't mean everyone should run out for a latte," said Frank Hu, senior author of the study and an HSPH associate professor of nutrition and epidemiology.
Scorpion Venom Attacks Bone Loss in Periodontal DiseaseA compound found in scorpion venom has inhibited bone loss in an animal model of advanced periodontal disease. It appears to be the first study to demonstrate that a potassium channel blocker--in this case, kaliotoxin--may be useful in treating the disease.The scientists, based at Forsyth Institute, induced the bone loss component of periodontal disease in rats and injected one group with kaliotoxin. After ten days, the experimental animals exhibited 84 percent less jaw bone loss than did the controls. The work is published in the January Journal of Bone and Mineral Research. According to principal investigator Paloma Valverde, kaliotoxin modulates inflammatory bone resorption by blocking the protein Kv1.3, a potassium channel involved in inflammation. She said that kaliotoxin decreases the expression of RANKL, a protein expressed on the surface of T cells that are present at high levels in periodontal disease. RANKL plays a key role in inducing osteoclasts to destroy bone. Kaliotoxin and other potassium channel blockers that target Kv1.3 may thereby reduce bone resorption. "We expect that kaliotoxin and other Kv1.3 blockers may also be used to prevent bone destruction in other inflammatory bone resorptive disorders such as osteo- and rheumatoid arthritis," said Valverde, who conducted her research as an instructor in oral biology at HSDM and Forsyth and has now joined Tufts University. "We are very excited because this is the first demonstration that this type of compound may be useful in treating periodontal disease," said Martin Taubman, HMS professor of oral and developmental biology at Forsyth and the institute's immunology chair, in whose lab the research was done.
Loss of Transcription Factors May Lead to Form of Muscular DystrophyThe genetic mutation associated with myotonic dystrophy has been known for years, but how the abnormality causes disease has remained in question. Researchers at HMS may now have discovered a part of the answer: the leaching of transcription factors from chromatin by mutant RNA. Their findings appear online in Science and in the Jan. 16 print edition.Myotonic dystrophy type 1 (DM1) is caused by a 10- to 1,000-fold increase in the number of CTG repeats in a region of the DM protein kinase (DMPK) gene. DM1 is the most common form of muscular dystrophy in adults. The mutation results in multiple abnormalities, including muscular dystrophy, myotonia, cardiac-conduction defects, diabetes, gonadal atrophy, and mental retardation. The connection between the mutation and its clinical manifestations has been elusive because the defect occurs in a part of the gene that is not translated into protein. It also has been hard to explain how such a spectrum of seemingly unrelated symptoms could stem from a single-gene disorder. The researchers, from the Harvard Institute of Human Genetics, have found a novel mechanism by which the RNA produced by a mutated DMPK gene may be the culprit. Alexander Ebralidze, HMS research fellow in medicine at Beth Israel Deaconess Medical Center; Richard Junghans, HMS assistant professor of medicine at BID; and colleagues have found that mutant DMPK RNA binds to several transcription factors and causes a redistribution of these factors away from the chromatin. This loss of transcription factors from active chromatin leads to decreased expression of several proteins that are involved in a range of processes. The researchers were able to show that one protein in particular, CLCN1, a chloride channel molecule whose loss has been associated with myotonia, could be restored to normal levels when its transcription factor was restored. This result suggests therapeutic options for DM1 through restoration of specific factors. In their study, the researchers found that more than 50 percent of cellular genes are depressed by the loss of transcription factors from chromatin. If transcription factor leaching does prove to be central to DM1's pathological mechanism, Junghans's group would like to explore which genes or transcription factors are critical to the disease phenotype. "This new understanding of myotonic dystrophy really demonstrates how far we've come from the old idea of 'one gene, one protein, one disease,'" Junghans said, "and, as our understanding grows, so does our arsenal of treatment possibilities." The investigators also hope to show that transcription factor leaching applies to another form of the disease, myotonic dystrophy 2 (DM2), caused by a set of repeats on a different chromosome from that affected in DM1. --Jennifer Altreuter |
