Research Notes

Stopping Ebola in Its Tracks Richard Preston brought the threat of emerging infectious diseases to the consciousness of his readers in The Hot Zone. The book graphically describes how the Ebola virus causes massive internal bleeding, which kills up to 90 percent of the people it infects. Now National Institutes of Health scientists are making promising advances to stop disease spread. Researchers have identified a viral protein that destroys endothelial cells, the cells that line the blood vessel walls, which may account for the gruesome way the virus kills (Z-Y. Yang et al., "Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury," Nature Medicine, 6:886-9, August 2000). Though Ebola outbreaks are not common or widespread, researchers can learn much about the pathogenicity of other viruses through studying Ebola. "We have learned by watching AIDS spread throughout the world that the time to develop vaccines or treatments for emerging viral infections is before they have blossomed," says Gary Nabel, director of the Vaccine Research Center at NIH. Nabel and his colleagues determined that of the seven gene products the virus encodes, glycoprotein (GP) on the virus surface mediated cytotoxic effects. The protein appears to target specific cell types, and subsequently causes damage to these cells when they synthesize this gene product. With the protein in hand, the researchers can probe the mechanism by which GP damages cells. They have narrowed the cytotoxicity to a particular region of the protein, which may help them identify its cellular targets within the host. "This might give us an opportunity to block that step with drug inhibitors or antibodies," says Nabel. --Nadia S. Halim Diverting Fat's Fate Images: Ormond MacDougald, University of MichiganTissue samples from experimental and control mice in the University of Michigan study show how expression of Wnt blocks formation of adipocytes. Understanding the pathway for fat cell development could help scientists learn how and why obesity occurs. Taking a step toward this goal, Ormond MacDougald, assistant professor of physiology at the University of Michigan Medical School, and his colleagues have identified a Wnt signaling pathway, probably mediated by Wnt-10b, that governs adipogenesis or fat cell development (S.E. Ross et al., "Inhibition of adipogenesis by Wnt signaling," Science, 289:950-3, Aug. 11, 2000). Scientists knew that Wnt proteins were involved in early cell development, but this study connects them to adipogenesis for the first time. Preadipocytes, precursor fat cells, can remain quiescent, multiply, or differentiate into adipocytes. The researchers found that Wnt signaling represses differentiation of preadipocytes by inhibiting two transcription factors: CCAAT/enhancer binding protein a (C/EBPa) and peroxisome proliferator-activated receptor a (PPARa). Furthermore, blocking Wnt signaling not only allowed preadipocytes to differentiate into fat cells, but it also caused myoblasts, which should form muscle cells, to switch their cell fate to fat. These findings suggest that both types of mesodermal cells, preadipocytes and myoblasts, resist entry into the adipogenic program by secreting a member of the Wnt family. "When we induced cells to differentiate by adding MDI (methylisobutylxanthine, dexamethasone, and insulin), Wnt-10b decreased in the cells immediately," says Sarah Ross, first author of the paper and graduate student in the MacDougald lab. Now the researchers are trying to determine what causes the decrease in vitro and what other agents might normally regulate Wnt-10b in vivo. They would also like to show that Wnt-10b will block fat formation in a developing mouse using a transgenic approach. --Nadia S. Halim Hair and Epidermis Share Progenitor Cells In the ongoing quest to chart the human body's storehouses of stem cells, a duo of dermatologists and their co-workers have identified progenitor cells in the "bulge" region of the hair follicle in mice that apparently give rise to both hair and epidermis (G. Taylor et al., "Involvement of follicular stem cells in forming not only the follicle but also the epidermis," Cell, 102:451-61, Aug. 18, 2000). In 1990, Robert M. Lavker, professor of dermatology at the University of Pennsylvania School of Medicine, and Tung-Tien Sun, professor of dermatology at the New York University School of Medicine, traced the progeny of bulge cells downward, where they give rise to the hair shaft. The observation that new skin in severely burned patients arises from surviving hair follicles led them to suspect that perhaps these "young transient amplifying cells" had another talent--regenerating the outer skin layer. The researchers used dual DNA precursor labels that are preferentially lost from rapidly dividing cells, persisting in stem cells and thereby highlighting them and their immediate progeny. The labels revealed two developmental trajectories. "A population of cells exists in the upper part of the follicle, above the bulge. We were able to tag only them. With time, we could trace the pathway of not just the follicle, but of cells that take up residence in the epidermis, where they continue to divide a few times. Bulge cells apparently give rise to both follicles and epidermis, which are completely different structures anatomically and biochemically," Lavker relates. But as is the way of science, he and Sun are trying to eliminate competing hypotheses. "We did not formally see one cell diverge to two fates. Maybe the bulge has two groups of undifferentiated cells. But that seems unlikely," concludes Lavker. Whatever the eventual conclusion of the story, the ability to track the source of skin regeneration is certain to have repercussions in understanding the etiology of skin cancers, and in suggesting ways that patients' own bodies can be tapped to heal wounds and recover from burns. --Ricki Lewis Reverse Thinking Going against 50 years of thinking in human genetics, researchers at the Whitehead Institute in Cambridge, Mass., recently suggested that the mutation rate in the human X chromosome is roughly equal to that of the Y chromosome (H.B. Bohossian et al., "Unexpectedly similar rates of nucleotide substitution found in male and female hominids," Nature, 406:622-5, Aug. 10, 2000). In 1947, renowned geneticist J.B.S. Haldane hypothesized that the mutation rate of the human male germ line is much higher than is the female, ever since making men the primary agents of evolutionary change. Several studies in primates have supported Haldane's assertion by showing that Y-linked genes evolve more rapidly. Using a novel approach, Whitehead scientists, led by David Page, a Howard Hughes Medical Institute investigator and professor of biology at Whitehead, came to quite a different conclusion. The researchers compared a portion of the human X chromosome that is known to have been copied to the Y chromosome 3 million-4 million years ago. The regions on the two chromosomes are now 99 percent identical; the 1 percent--about 49,000 base pairs--that has diverged represents newly acquired mutations. Investigators counted similar numbers of mutations in that crucial base pair area; they used gorilla and chimpanzee X chromosomes as a reference to decide whether the mutations detected arose on the human X or Y chromosome. Page notes that unlike previous studies, the Whitehead study intentionally scrutinized only noncoding junk DNA to ensure that the mutation count would not be biased by the influence of natural selection. "The design of our experiment is far simpler and more transparent than anything that has come before," he claims. Page also suggests that the findings could help identify the genetic underpinnings of several diseases by elucidating the relative contributions of sperm and eggs in carrying new mutations in the genome as a whole. --Eugene Russo

Research Notes

Stopping Ebola in Its Tracks

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