Research Notes

Brain Disease Research Advances with Gene Chips Though there is no cure for the millions of Americans with epilepsy, recent advances using gene chip technology may have found a key to treatment for those recovering from seizure trauma. Researchers led by the Salk Institute for Biological Studies in La Jolla, Calif., report on using the gene chip technology that determines whether a gene is turned on or off by measuring its ability to bind to the corresponding DNA sequences on the chips. They compared the activities of 13,000 genes in two inbred strains of mice that show significant genetic variability, including in the ability of their brain cells to survive after a seizure (R. Sandberg et al., "Regional and strain-specific gene expression mapping in the adult mouse brain," Proceedings of the National Academy of Sciences, 97:11038-43, Sept. 26, 2000). They were able to pinpoint several genes that varied between the strains after seizure. Predisposition to conditions such as epilepsy, alcoholism, and mental illnesses such as schizophrenia is thought to depend on specific combinations of genes, and previously available techniques could examine only individual genes or small numbers of genes at once. Carrolee Barlow, assistant professor at the Salk Institute, explains, "With the human genome available, we now know the sequence of tens of thousands of genes but not what they do. Gene chip technology allows us to look at many genes at once and screen for the handful of genes that are turned on at any given time." The team, which included University of California at San Diego and Novartis Research Foundation in San Diego, monitored gene activity in the brains of both mouse strains following drug-induced seizures. They found that almost 50 genes were turned on in the hippocampus of the resistant strain vs. only a dozen in the sensitive strain. Says Barlow, "The next step will be to figure out what the genes are doing--and if having those genes turned on actually protects the brain cells. If so, then we might be able to find a way to artificially turn on the appropriate genes or design drugs that mimic the effect to prevent the cells from dying." --Kate Devine Nothing to Sniff At Last year, Elan Pharmaceuticals of South San Francisco, Calif. reported the efficacy of an Alzheimer's disease (AD) vaccine in mice (E. Russo, "Alzheimer's Vaccine," The Scientist, 13[15]:39, July 19, 1999). By priming the immune system with injections of a synthetic form of the neuron-suffocating amyloid plaques characteristic of the disease, researchers stymied plaque formation in a mouse model engineered to mimic AD pathology. Using the same mouse model, researchers at Brigham and Women's Hospital in Boston recently got encouraging results using a nasal spray version of a similar AD vaccine (H. Weiner et al., Annals of Neurology, 48:567-9, October 2000). Dennis Selkoe and Howard Weiner, co-directors of the Center for Neurologic Diseases at Brigham and Women's, collaborated on the project. The research, which actually started prior to Elan's, was inspired by Weiner's nasal and oral vaccine work in autoimmune diseases, such as multiple sclerosis, and Selkoe's work on beta-amyloid. Weiner reasoned that similar treatments might have an impact on AD, which, like autoimmune diseases, has an inflammatory component. Nasal vaccines are thought to be better tolerated than injections. However, injections reduced plaque burden more than the nasal spray, possibly due to a poorer antibody response or, says Weiner, to different experimental conditions. Weiner's group plans to conduct a Phase I trial within the next year; Elan, which has acquired rights from Brigham and Women's to commercialize any future nasal vaccine, is independently conducting a Phase I trial for its injection vaccine. Investigators need to not only demonstrate negligible toxicity, but understand the immunization mechanism and the effect of immune reactivity on AD pathogenesis. "The vaccination approach is really a new direction for Alzheimer's," says Weiner. "It really offers a therapeutic and mechanistic opportunity that didn't exist before." --Eugene Russo Cure for Metastatic Kidney Cancer? In mid-September, newspaper and TV journalists touted another "miracle" in cancer research. National Institutes of Health researchers had transfused lymphocytes and hematopoietic stem cells from tissue-matched siblings into 19 patients with metastatic kidney cancer, which has a median survival time of less than a year. The result: Nine patients were alive from 287 to 831 days after transfusion, and most patients showed substantial or complete regression of their metastases (R. Childs et al., "Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation," New England Journal of Medicine, 343:750-8, Sept. 14, 2000). But news reports weren't very forthcoming on why this therapy worked. Richard Childs, lead author and a senior investigator at the National Heart, Lung, and Blood Institute, suggests an explanation: Chemotherapy first suppressed, and the transfused lymphocytes then destroyed, the patients' immune systems. "The hypothesis was that the tumors were poorly immunogenic to start with," he says; the patients' immune systems also likely "became tolerized to the tumor" so that they failed to mount cytotoxic responses. The researchers' idea was to "come in with a completely new immune system, non-tolerized, that would hopefully contain the T-cell repertoire necessary to target and attack the tumors." Graft-vs.-host disease, which beset 10 patients and was fatal to one, was the major drawback. Childs says that a new trial, which began six months ago, should eventually apply the therapy to 15 other solid tumors, including those of the esophagus, stomach, liver, colon, prostate, bladder, and lung. A melanoma study is also under way, but he notes that this tumor "tends to proliferate much more quickly than kidney cancer" so that donors' immune systems may not have the three to six months they need to supplant recipients' immune systems, after which therapy becomes most effective. --Douglas Steinberg Terminator Jellyfish Invade Gulf Coast The shores of Alabama, Louisiana, Florida, and Mississippi recently hosted an influx of a usually rare visitor: medusae of the jellyfish Phyllorhiza punctata. Fortunately the sting is mild, but the animals have been clogging the nets of fishers and gobbling shrimp larvae and fish eggs, earning them the name of "terminators." Researchers at the Dauphin Island Sea Lab of the University of South Alabama think the jellyfish, normally residents of Australia, may have reached the Caribbean as stowaways in the polyp stage on ships passing through the Panama Canal. They then drifted to the Gulf Coast, where the dry, hot summer coaxed the population to swell. But come September, they were gone. "These animals are seasonal and have all but disappeared completely. Future impacts on fisheries will depend on whether the animals show up [again] in large numbers. We await happenings next year," says William Graham, assistant professor of marine sciences and senior marine scientist at the lab. Although the species has been seen off the Alabama coast before, it has not, to Graham's knowledge, appeared in such large numbers. --Ricki Lewis

Research Notes

Brain Disease Research Advances with Gene Chips

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