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RNA BEGINNINGS Research that began as a quest to see how plant cells become infested with viruses ended in questions about the origins of life. In that quest, Steven A. Lommel of North Carolina State University in Raleigh and colleagues used a reporter gene to follow the viral activity in its host. But the gene didn't light up as expected during their study of the genome of a red clover necrotic mosaic Dianthovirus (RCNMV) genome [T.L. Sit, et al, Science, 28 :1829-32, Aug. 7,1998]. The genome contains two RNA components--RNA-1, which encodes the virus's polymerase and the viral protein coat, and RNA-2, which encodes the movement protein that allows cell-to-cell infection. They discovered that a specific base-pairing interaction occurs between RNA-2 and RNA-1 that actually activates transcription leading to the making of the viral protein coat. "Amazingly, the virus doesn't express the gene unless the RNA is present," Lommel maintains. Scientists have previously shown that RNA can perform many functions once attributed only to DNA, including catalyzing reactions and forming peptide bonds between amino acids. This study adds another activity to the list, Lommel notes. The growing number of activities attributed to RNA's capabilities means the chemical could, in theory, perform many of the functions essential to give rise to life. NEURONS AND PARKINSON'S DISEASE Parkinson's disease is a prime target of cell implant technology because the site and biochemical nature of the defect are well known--loss of dopamine-producing neurons in the substantia nigra. Now, researchers at the National Institute of Neurological Disorders and Stroke have nurtured cells from rat embryos destined to develop from dopamine-producing neurons into aggregates of neurons (L. Studer et al., Nature Neuroscience, 1 :1-6, August 1998). These specialized cells not only connect with each other, but, when implanted into Parkinsonian rats, improve their mobility. "This is the first demonstration that we can maintain cells dividing in culture efficiently and get them to differentiate into a specific neuron type in the brain," explains Ronald McKay, chief of the laboratory of molecular biology at NINDS. Rats received six or seven spheres each, totaling 300,000 to 400,000 implanted cells. The technique has two steps. "A 100-fold expansion takes about one week, in the presence of fibroblast growth factor. In the second phase we remove the growth factor, and the cells differentiate and form aggregates. These balls of cells fit a bore needle so they can be directly grafted," says McKay. The next step is to discover how the implants fit into their new homes. "We would like to optimize the ability of the cells to connect with the host. This is what's needed to make grafting a viable technology," McKay adds. KIDNEY RESEARCHERS: From left to right, John R. Asplin, Sokalingum N. Pillay, and Fredric L. Coe of the University of Chicago HALTING KIDNEY STONES Every person's kidneys are supersaturated with calcium and oxalate. According to the basic laws of chemistry, crystals, more commonly known as kidney stones, should form routinely. More people don't develop the stones because most persons flush out microscopic calcium oxalate crystals when they urinate, and because several proteins in the kidney aid in slowing or stopping crystal formation. University of Chicago researchers report (S.N. Pillay et al., The American Journal of Renal Physiology, 44 :F255-61, Aug. 1998) that an anti-inflammatory protein called calgranulin appears to be particularly adept at halting stone growth. "For decades scientists have known that the kidney has to mount a defense against crystals--otherwise it would destroy itself," notes senior author Fredric L. Coe, a professor of medicine and physiology and chief of nephrology at the University of Chicago. "But the nature of the molecules [involved] has been quite unclear." After examining the few anti-crystal molecules already identified, lead author Sokalingum Pillay, a research associate and assistant professor of medicine at the University of Chicago, guessed that they might belong to a class of proteins known as S100. Much to his surprise, a screening for the S100 class in human urine turned up the sequence for calgranulin, a protein previously identified only in white blood cells. "Of patients with stones, about 35 percent of their relatives will eventually become stone-formers," explains Coe. "One of the really immediate things we're considering, is...[to] use calgranulin as a reagent to find people at risk." Coe and Pillay are currently organizing a three-year study that's slated to begin in six months. In other future studies they hope to use a calgranulin-based drug to treat kidney stones. CELL CYCLE DISRUPTION BEHIND ALZHEIMER'S? Using an approach that will become commonplace in the post-genome project era, researchers at the University of Rochester have compared the expression of 20 genes in neurons from brains of people who died of advanced Alzheimer's disease to those from people in presymptomatic stages when they died of other causes (N. Chow et al, Proceedings of the National Academy of Sciences, 95 :9620-5,1998). "Most researchers take a piece of tissue, grind it up and perform tests. But it's hard to tell the differences between cells if you analyze them together," says professor of neurobiology and anatomy Paul Coleman. The five genes expressed only in the late-stage cells suggest that an inappropriately activated cell cycle may play a role in the disease, says Coleman, cautioning that this idea is still in "the arm-waving stage." "Something goes on in the brain of a person with Alzheimer's disease that tells neurons to revert to a more primitive state, when the brain is first forming and cells are dividing. Since neurons are post-mitotic, if they get a signal to divide, they may get part way down the pathway, reach a cell cycle checkpoint, then realize that things are not proceeding the way that they should, and commit cell suicide," he speculates. Taking such "molecular snapshots" of the same cell type at different points in pathogenesis can reveal biological markers for developing early diagnostics, and identify potential gene therapytargets. Theteam is already taking 96-gene snapshots. GREEN CHEMISTS: Tomas Hudlicky and Mary Ann Endoma of the University of Florida CHEMISTRY GOES GREEN Fueled by grants and awards from the Environmental Protection Agency (EPA), President Bill Clinton's "Green Chemistry Challenge" appears to be making headway toward its goal of promoting the development of new chemical technologies that help to prevent pollution. Among numerous examples of such commercially viable research is that of University of Florida professor of chemistry Tomas Hudlicky. His laboratory uses a mutant form of the common bacteria, Pseudomonas putida, to biocatalytically degrade such toxic aromatic compounds as dicholorbenzenes, napthols, and biphenyls that arise from natural resource production and industrial outflow, among other sources. Through the lab's process of whole-cell fermentation, these toxic compounds yield synthons useful in manufacturing carbohydrates and medicinally important alkaloids. "We use recombinant strains of the bug, which basically express only the enzyme we want the transformation to be directed by," Hudlicky explains. His work--which has resulted in two commercially available products and 10 patents with various partners--has been continuing since the late 1980s, even before EPA's green chemistry program began in 1991. "He is one of our earliest academic supporters," acknowledges program coordinator Tracy Williamson. In late June, EPA announced this year's winners of the Green Chemistry Challenge Awards. Three academicians were honored: chemistry professors Karen Draths and John Frost of Michigan State University for their use of microbes as environmentally benign catalysts in the synthesis of industrial chemicals; and Stanford University chemistry professor Barry Trost for developing the concept of "atom economy," which measures cost-effectiveness in chemical manufacture by accounting for the volumes of both product and waste generated. BRAINY HORMONE A man facing a cardiac operation that is likely to cause some degree of brain damage may one day receive neuroprotection with a single injection of the "female hormone," estrogen. That is the hopeful scenario arising from findings by a research team in the department of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine. Earlier this year, the group showed that estrogen reduces brain damage from stroke in female rats by about two-thirds compared to males (N.J. Alkayed et al., Stroke, 29 :159-65, 1998). Now, the researchers have shown that male rats treated with a shot of estrogen prior to an induced stroke suffer about half the brain damage of untreated males (T.J.K. Toung et al., Stroke, 29 :1666-70, 1998). "How it works, of course, is a very important question," notes co-author and department vice chairman Richard J. Traystman. Estrogen is a known scavenger of oxygen free radicals produced during ischemia, he says. It also may have important vasoactive properties. Senior author Patricia D. Hurn has obtained female mice with their estrogen receptors knocked out, but with plenty of the hormone remaining in their bloodstream. She wants to determine whether estrogen's neuroprotective effects are mediated by the vascular system as well as by genetics. Traystman asks another key question: "How long after stroke can you give estrogen and still have it be effective?" He expects other research being conducted by the team to provide the answer.

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August 1998

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