Research Briefs

Risky Trials Could Herald Cure for Prion Disease Patients with Creutzfeldt-Jakob disease generally face inevitable neurological decline and death. But, researchers are following closely the case of UK teenager Jonathan Simms, whose symptoms have been halted after he received 12 intracerebral injections of pentosan polysulfate (PPS) that started in January 2003. "By rights we would have expected him to have died eight months ago," says Stephen Dealler, a consultant microbiologist at East Lancashire Hospital in the UK, who was involved in the treatment. "If anything he's slightly better." According to Dealler, PPS has a double action. By sticking to the heparin binding sites of normal PrPc prion molecules, PPS prevents more of them from being converted into the PrPsc form associated with neural degeneration in prion disease. But PPS also appears to prevent the prions that have already converted into the PrPsc form from causing further brain damage. PrPsc stimulates inflammatory molecules which also operate through heparin binding sites, says Dealler. Fred Cohen, collaborator with Nobel Laureate and pioneer of the prion hypothesis Stanley Prusiner, cautions against overexcitement on the basis of a single isolated test. Large-scale trials are needed, but these would be difficult because of the intracerebral delivery, says Cohen. According to Dealler, the boy's father was determined that scientists pursue this course in this case. Says Cohen, "It is one thing to be heroic in a small number of cases." Approval for the treatment has since been granted in at least three more patients with prion diseases. --Philip Hunter Chicken Toe-Growth Explained ©2003 Elsevier Rather than questioning fowl motives, UK developmental biologists have delved more into the physiological quandaries of crossing the road. Cheryll Tickle and Juan Jose Sanz-Ezquerro, while at the University of Dundee, characterized several key players in the signaling cascade that controls phalanx growth and digit tip formation in chicken feet.1 According to their model, fibroblast growth factor8 (Fgf8), produced in the limb bud, controls phalanx elongation and possibly number (unlike humans, chickens have a variable number of phalanges in each toe). As long as Fgf8 is being expressed, the phalanges continue growing, but when Fgf8 is shut off, the mechanism controlling tip formation, which involves Wnt (wingless) proteins and produces special structures such as claws, takes over. By inserting beads containing Fgf8 agonists and antagonists into the digits, Tickle and Sanz-Ezquerro could manipulate phalanx length. "These results are cool, but there are caveats," says John Fallon, molecular biologist at the University of Wisconsin, Madison, who has also researched phalanx development. "When you put a bead into a digit that inhibits Fgf8 signaling, you've altered the signaling center." Though involved in elongation, Fgf8 does not control segmentation and knuckle formation, says Fallon: "There is no evidence that Fgf8 coming from the apical ridge has anything to do with patterning." --Maria W. Anderson 1. J.J. Sanz-Ezquerro, C. Tickle, "Fgf signaling controls the number of phalanges and tip formation in developing digits," Curr Biol, 13:1830-6, October 2003. A Kinesin Conundrum A new kinesin motor crystal structure could reveal how these intracellular cargo carriers move. Sharyn Endow of Duke University Medical Center and Hee-Won Park of St. Jude Children's Research Hospital, Memphis, Tenn., reported a structure of the protein Ncd, which moves toward the stable minus end of microtubules; conventional kinesin proteins travel toward the plus end.1 "It's the first structure that suggests that Ncd might really have a fundamentally different mechanism than the plus-end motors," says F. Jon Kull of Dartmouth College. Kinesin motor proteins use energy derived from ATP binding and hydrolysis, but it's uncertain how. Endow and Park mutated Ncd to destabilize the ADP state of the protein, and their data indicate motor movement during ADP release, contrasting with an earlier model suggesting that rotation occurs during ATP binding. Andreas Hoenger of EMBL, Heidelberg, Germany, argues that the structure may represent a transient state and that the Ncd mutation does not represent the protein's actual native conformation. Endow counters that X-ray crystallography of the wild-type protein revealed the same, albeit less well-ordered or stable structure. In the end it's a matter of interpretation. "It's just a question of ... whether the power stroke is during the loss of ADP or during the binding of fresh ATP," says Linda Amos of the Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. Kinetic experiments, she says, might distinguish the difference. --Aileen Constans 1. M. Yun et al., "Rotation of the stalk/neck and one head in a new crystal structure of the kinesin motor protein, Ncd," EMBO J, 22:5382-9, 2003. function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

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