Notebook

PHANTOM PAIN GUT-WRENCHING STORY PACEMAKER IN THE BRAIN THE SCOOP ON DINO DINING SUMATRAN TIGER, A DISTINCT SPECIES FUNGUS AMONG US HONORABLE QUARTET FROM GM PAIN EXPLAINED: Washington University's Min Zhuo found that a region of the brain in rats could activate neurons in the spinal cord, possibly causing feelings of pain without any external stimulation. PHANTOM PAIN Results from a Washington University study bring up new questions about your high-school gym teacher's old proclamations that your pain is all in your head. A research team found that chemical signals from the brain can condition nerve synapses in the spinal cord so that pain persists even in the absence of a stimulus. While investigators have known that the brain effectively reduces pain by inactivating synapses, few have considered the effect of the brain on enhancing signals of pain throughout the nervous system. Min Zhuo, an assistant professor of anesthesiology at WU, found that a region of the brain in rats could activate neurons in the spinal cord, causing feelings of pain without an apparent source (P. Li, M. Zhuo, Nature, 393: 695,June 18,1998). In the study, Zhuo, along with research assistant Ping Li, showed that the rostroventral medulla region of the brain sends a serotonin signal to the dorsal horn of the lumbar spinal cord. Here, the signal reactivates so-called "silent," or inefficient, synapses at nerve junctions. The finding is significant because it provides insight on why some patients continue to suffer pain even when the stimulus is gone, Zhuo says. For example, cancer patients often have persisting pain even after tumors are removed. "Through the process we call 'long-term potentiation,' neurons in the spinal cord become efficient for transmitting pain," He says, "Once 'silent' synapses have been activated during tissue or nerve injury, they tend to remain functionally active and continue to send messages to the brain even when there is no stimulus to speak of." Zhuo says the research could have significant clinical implications because it suggests new targets and pathways for therapies aimed at chronic pain. GUT-WRENCHING STORY A Stanford University postdoc drank a cloudy, salty solution of enteropathogenic E. coli in the name of science--and a story. Kristin Weidenbach, now a Boston-based science writer, decided to participate in the study, whose aim was to determine the mechanisms by which the diarrhea-causing bacteria become virulent. Some volunteers ingested wild-type E. coli, others gulped mutant versions that produced more pili, the bristly filaments protruding from the bacteria's cell walls, and another group consumed a mutant without pili. In test tubes, bacteria with too many pili clump together, don't disperse and don't twitch as much. The study was designed to see if these characteristics would have any effect on causing diarrhea in hosts. Weidenbach and the other volunteers did not know in advance which strain they would swallow. "There was a bit of a psychological barrier to overcome," she recalls. Weidenbach, who documented her three-day ordeal for a Stanford publication, was fortunate. She received the highest concentration of a mutant strain and was only ill briefly. The study concludes that the pili and pili-related genetic domain BfpF are indeed responsible for the bacteria's' dispersal and contribute to its virulence (D. Bieber et al., Science, 280:2114-8, June 26, 1998). PACEMAKER IN THE BRAIN The heart's pacemaker is familiar: a group of cells that generates a coordinated electrical activity that spreads throughout the organ. Cells in the brain perform the same function, report a team from Columbia University (B. Santoro et al, Cell, 93:717-29, May 29, 1998). "A 'pacemaker' means that cells are spontaneously active, without exogenous stimulation. In some regions of the brain, pacemaker functions are normal, such as the regions that control respiration. Spontaneous activity there is why you do not need a conscious effort to breathe," explains Steven Siegelbaum, a professor of pharmacology at the Howard Hughes Medical Institute and the Center for Neurobiology and Behavior. He and University Professor Eric Kandel and others identified a family of genes, in mice and humans, some of which appear to set the pace in both the brain and the heart. The genes encode protein channels in nerve and muscle cell membranes that admit potassium and sodium ions, which initiate electrical impulses. The work has both clinical and basic research implications. Excess brain pacemaker activity might cause seizures, points out Kandel, and "one might decrease the tendency to seize by suppressing this current," he says. Conversely, a sluggish pacemaker might adversely affect thinking ability or alertness. "These studies show that proteins that control pacemaker activity in the heart and the brain belong to the same gene family. This indicates a profound evolutionary relationship between pacemaker channels in the heart and the brain," Kandel adds. THE SCOOP ON DINO DINING A slightly bigger-than-a-breadbox ovoid mass discovered in weathered mudstone in the Frenchman formation in southwestern Saskatchewan (K. Chin et al, Nature, 393:680-2, June 18, 1998) is the remains--a coprolite--of a Triceratops meal. "This coprolite is much larger than any previously ascribed to a carnivorous animal," says Gregory Erickson, a postdoctoral fellow at Stanford University and part of the research team led by Karen Chin of the U.S. Geological Survey in Menlo Park, CA. The object's size and bony contents identify the source as a meat-eater, and the prime candidate in the area is none other than Tyrannosaurus rex. The dropping reveals much about its dining habits. "The bone was broken up when the carnivore ate its prey. This means that it had the capacity to smash up bone by crushing and biting," explains Peter Andrews, a paleontologist at the Natural History Museum in London, who co-authored an editorial, "101 Uses for Fossil Coprolites" (P. Andrews, Y. Fernandez-Jalvo, Nature, 393:629-30, June 18, 1998). Erickson anticipates future fecal finds. "With more coprolites we will be able to study the T. rex diet. Was it eating lots of species, or was it specializing? Was it eating animals of any particular age? If it ate animals that typically die of attrition, such as the very young and very old, it might suggest scavengry. But if it ate animals of all ages, it might suggest predatory activity." SUMATRAN TIGER, A DISTINCT SPECIES Deciding whether groups of animals are distinct species used to be a simple matter of observing who could mate with whom. Enter molecular genetics. Shared unusual DNA sequences, plus physical resemblances and occupation of the same habitat, can distinguish species. So it is with tigers. Of the five living subspecies, the Sumatran tiger is the smallest and the rarest, with only 500 animals in the wild and 235 in captivity. Joel Cracraft, a curator at the American Museum of Natural History, and colleagues at the New York Botanical Gardens, DePaul University, and the Wadsworth Center at the New York State Department of Health, compared mitochondrial DNA (mtDNA) sequences among four tiger types and a lion, and found three genetic markers unique to Sumatran tigers. The species-defining event probably occurred 6,000 to 12,000 years ago, when Sumatra separated from Asia. The island tigers diverged genetically from their mainland counterparts, as has happened with the Sumatran rhinoceros. Identifying the uniqueness of the rare tiger has implications for species conservation policy. If all tiger types were the same species, then efforts would attempt to increase their genetic diversity. "But given the new information, conservationists will not want to breed Sumatran individuals with Indochinese or Bengal tigers. We now need to preserve aspects of the species," says Jeffrey Vaughn, a research assistant at the Wadsworth Center who compared the DNA sequences. The work is published in the June issue of Animal Conservation (Issue 2, No.1, Zoological Society of London). FUNGUS AMONG US A 'clinical trial' is under way to restore a major tree species to the eastern United States. Until 1900, one in four Appalachian trees was chestnut. The fungus Chryphonectria parasitica, accidentally introduced into New York, then decimated mature chestnut trees and by 1940 none remained. The tree is still around, however; saplings sprout from diseased stumps only to succumb later. A team led by Sandra Aganostakis of the Connecticut Agricultural Experiment Station in New Haven and Donald Nuss of the University of Maryland Biotechnology Institute in College Park may break the cycle. The fungus has a pathogen of its own, called Hypovirus, which disrupts a cyclic AMP-mediated signal cascade necessary for virulence. Unfortunately, aspects of the fungal life cycle impede Hypovirus spread. The problem was solved by transforming fungal cells with a cDNA version of the hypoviral RNA genome engineered into a plasmid. Once the cDNA integrates into Chryophonectria 's chromosomes, transmission is easier. The integrated Hypovirus isn't lethal but attenuates the fungus' virulence. A bioremediation scheme is obvious: collect fungus from an infected area, transform it with the Hypovirus construct, grow up spores and re-introduce them into the forest. Echoing the way sterile males are used to control medfly, the transformed fungus should fuse with its disease-causing brethren, rendering the population less harmful. To test the strategy, says Nuss, the team had to 'identify a site where you have optimum conditions for it to work,' like a clear-cut where chestnut sprouts grow rapidly, then go to more challenging conditions. Previous efforts gave mixed results, but with a successful new trial future hikers may one day again rest under shady chestnut trees. HONORABLE QUARTET FROM GM In June, the General Motors Cancer Research Foundation honored the efforts of four scientists. The researchers shared $750,000 in prizes. Rodney Winters of the University of California, Los Angeles, won the Charles F. Kettering Medal and a $250,000 prize for his demonstration that proliferating cells are less able to repair themselves after radiation injury. Based on this observation, he devised a treatment for cancer that delivers higher doses of radiation over shorter intervals to malignant tumors. Suzanne Cory of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, and Stanley J. Korsmeyer of the Washington University School of Medicine, St. Louis, shared the Charles S. Mott Medal and a $250,000 prize for research on the cause and prevention of cancer. The two researchers independently discovered that the BCL-2 gene encodes for a protein that induces cancer by suppressing programmed cell death, or apoptosis. H. Robert Horvitz, a Howard Hughes Medical Institute investigator at the Massachusetts Institute of Technology, captured the Alfred P. Sloan Medal for research in basic science. The foundation cited him for his investigations that have identified many genes acting in signaling pathways for apoptosis. Although scientists studying apoptosis captured two of the three awards, the foundation made no deliberate effort to focus on a specific area of research. "It was really coincidence that two of the awards were for this kind of research on apoptosis," Samuel A. Wells, president of the foundation, says. "But this coincidence certainly shows what an important biological phenomena it is and how progress in this field has been stunning." Horvitz, who has authored some of the most cited papers on apoptosis, says awards like the Sloan Medal make him reflect on the enormous contribution of all investigators to the advancement of science. "Awards like this really recognize the efforts of a large number of individuals," he says. "Discoveries never happen in isolation. When getting an honor like this, I have to think of every graduate student, postdoctoral researcher, and investigator who has worked to get this phenomenon recognized as a major part of many different biological processes."

Notebook

The Scientist Staff

Jul 5, 1998

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