Notebook

Peanuts may be losing their bite PEANUT ALLERGY VACCINE Peanuts are more than just an annoyance on airplanes--for a few dozen people each year, they cause deadly anaphylactic shock. The only protection is knowledge of one's allergy and avoidance of the offending food. But most peanut-associated allergic deaths occur from peanut extracts added to prepared foods--additives that sometimes remain unlisted on labels. A peanut allergy vaccine could prevent such deaths. Kam Leong, a professor of biomedical engineering at the Johns Hopkins University School of Medicine and coworkers encapsulated a plasmid-borne gene encoding a major peanut antigen in the biodegradable polysaccharide and crustacean-extract chitosan, and fed it to sensitized mice. "The DNA is delivered to cells lining the gastrointestinal tract. The gene product of this DNA is the peanut allergen, which after processing by the cells is presented to the immune system. Acting as a vaccine, this processed allergen is speculated to shift the immune system away from an allergic response," explains Leong. Antibody levels reflect a blunted allergic response, and fewer of the animals given the experimental vaccine (compared to a control) succumbed after consuming peanut chow (K. Roy et al., "Oral gene delivery with chitosan-DNA nanoparticles generates immunologic protection in a murine model of peanut allergy," Nature Medicine, 5 [4]:387-91, April 1999). --Ricki Lewis IN A WHIRL If trout fishing in America strikes you as a rainbow-free experience these days, blame whirling disease. The parasite Myxobolus cerebralis, introduced from Europe four decades ago, has been devastating populations of rainbow and cutthroat trout and chinook salmon in the Pacific Northwest and Northeast. Now, with $150,000 from the nonprofit Whirling Disease Foundation of Bozeman, Mont., scientists are looking for a genetic fix. The lab of Peter Parham, a professor of structural biology and microbiology and immunology at Stanford University, is collaborating on the project with University of California at Davis professor of veterinary medicine and epidemiology Ronald Hedrick and colleagues. They will study controlled infections in trout and salmon, including species that rarely show signs of the disease, and will sequence genes of the major histocompatability complex (MHC) in a search for immune system resistance. The parasite enters young fish through the skin and rapidly multiplies, exerting central nervous system pressure that makes the fish whirl erratically, and eventually die of starvation or predation. Humans have about a dozen MHC genes, all found on the same chromosome and all related to immune response. "We know rather little about the fish immune system," acknowledges Parham, including whether trout and salmon MHC genes will be found on one or more chromosomes. But similarities across vertebrate species lend hope that a resistant fish gene or genes can be identified that could be bred into the victimized species. "We hope to have some studies done within two years," he says. "I'm anticipating positive results." --Steve Bunk REEVALUATING HERPES B Between 35 and 40 virologists, physicians, veterinarians, and representatives from the Centers for Disease Control and Prevention, National Institute of Occupational Safety and Health, and seven regional primate centers met in Atlanta January 26-27 to discuss new guidelines for prevention and treatment of herpes B virus. The meeting was prompted by the December 1997 death of primate worker Elizabeth Griffin at Atlanta's Emory University Hospital after she was hit in the eye with body fluid from an infected rhesus monkey (B.A. Palevitz, R. Lewis, "Death raises safety issues for primate handlers," The Scientist, 12 [5]:1, March 2, 1998). According to David Davenport, a B virus expert who attended the meeting, the Griffin case was important in getting people to rethink disease risks and treatment. We now know that "all exposures carry a risk," says Davenport. Consequently, situations previously considered low risk should be moved to a moderate or high-risk category. Because Griffin was the first documented transmission of B virus through an intact mucous membrane, risk assessment should be based on what a worker does and not just specific exposure incidents, which could be innocuous. The Atlanta meeting charged committees with writing specific proposals, which will be compiled and evaluated by Jonathan Richmond, meeting organizer and director of CDC's Office of Health and Safety. "I imagine a summer completion," notes Richmond. A final report will be published in an as-yet unspecified journal. Davenport thinks the panel will probably recommend greater communication between primate centers, attention to workplace safety, and more liberal treatment with antiviral drugs. --Barry Palevitz NOT SLEEPLESS OVER RITALIN A more effective form of the drug Ritalin (methylphenidate) that may produce fewer side effects could be available soon to treat attention deficit/hyperactivity disorder (ADHD). The analogue is ready for commercial scale-up, according to a paper presented on March 22 at the American Chemical Society conference in Anaheim, Calif. Research by Jeffrey Winkler and his colleagues at the University of Pennsylvania indicates that the same new analogue of the drug, based on a new synthesis developed in Winkler's laboratory, could be used in anticocaine therapy. Ritalin, prescribed for approximately 1.5 million elementary and secondary school students, has a market value of $500 million per year. Its most common side effects are nervousness and insomnia. Synthesizing "chiral Ritalin" from inexpensive, nonchiral starting materials is the key to the drug's improvement, said Winkler. Drug compounds have mirror images, known as being right- and left-handed, he explained. Often, only one of the hands is biologically active, delivering the desired pharmacological agents. If a racemic (both-handed) drug can be made chiral (one-handed), the result is usually a lower dosage with fewer side effects. Ritalin works at the same receptor in the brain as cocaine. As a result, Winkler's group is examining the new analogues in cloned cell lines to see if they can be used to block the uptake of cocaine in that area of the brain, without inhibiting the normal flow of dopamine, a chemical neurotransmitter vital to the proper functioning of the central nervous system. Winkler claimed that his group has "just developed the most potent compounds in the literature, which have a ten-to-one selectivity for inhibiting cocaine without interfering with dopamine," but the anticocaine effects of the analogue have yet to be studied in animals and humans. --Ilene Schneider CHOLESTEROL BUSTERS Cholesterol-reducing properties and other health benefits may be found in limonoids, the compounds in the peels of citrus fruits that produce a bitter taste, as well as in the blue-green alga Aphanizomenon flos-aquae (AFA), according to papers presented at the American Chemical Society conference in Anaheim, Calif., March 21-25. Elzbieta M. Kurowska of the University of Western Ontario in Canada observed a reduction of low-density cholesterol in rabbits after substituting orange juice and grapefruit juice for water. Testing of the limonoids in the juices suggested that the compounds "could contribute to cholesterol-lowering action of citrus juices," she said. Her research suggested that limonoids could be liberated from glucosides in the juices by the action of bacteria in the digestive tract. More than a dozen research papers presented at the conference demonstrated other properties of limonoids, including their ability to act as anticancer agents in some animals and their value as "potent inhibitors of proliferation" of human breast cancer cells in culture, according to Najla Guthrie, also of the University of Western Ontario. Christian Drapeau of Cell Tech in Klamath Falls, Ore., has confirmed that AFA taken as a dietary supplement can lower cholesterol in animals and help to maintain cholesterol within a healthy range. Already available on the market for that purpose, AFA contains significant amounts of polyunsaturated fatty acids (PUFAs), which appear to be well absorbed by animals. Research conducted during the past decade has indicated that PUFAs reduce blood cholesterol and that PUFA deficiency is linked with cardiovascular disease, chronic fatigue syndrome, certain forms of cancer, and attention deficit /hyperactivity disorder (ADHD). Drapeau cautioned that "we are currently doing studies to determine if the effects of AFA in cholesterol in rats will translate to humans." --Ilene Schneider Thomas R. Cech HOWARD HUGHES HELM: Nobel laureate Thomas R. Cech, a professor of biochemistry, biophysics, and genetics at the University of Colorado Health Sciences Center, will become the next president of the Howard Hughes Medical Institute (HHMI), but he will continue to supervise research in Boulder. Cech's Colorado research involves performing X-ray crystallography of large catalytic RNA molecules, as well as discerning the structural subunits of telomerase. As president of HHMI, Cech plans to expand the institute's work in structural biology and bioinformatics. "Computers have collided with biology in a major way," Cech notes. He would like to fund more structural biology research through the institute as well as expand educational efforts in the field. "Graduate students now are spending about half of their time in front of computers. And they are not even bioinformatics students. They are molecular biology students." Cech plans to log plenty of computing time himself by monitoring his Colorado colleagues' research by e-mail after he succeeds Purnell W. Choppin next January. --Paul Smaglik ROPING DOPAMINE Whether in the inhibited motor activity of Parkinson's disease, or the nervous tics of Tourette's syndrome, or the hyperactivity of schizophrenia, abnormalities in striatal neurons of the forebrain are involved. Dopamine is the key neurotransmitter modulating striatal neurons. But what, in turn, regulates dopamine? New findings show it's the chemical anandamide (A. Giuffrida et al., "Dopamine activation of endogenous cannabinoid signaling in dorsal striatum," Nature Neuroscience, 2 :358-63, April 1999). Senior author Daniele Piomelli, an associate professor of pharmacology in the University of California at Irvine's College of Medicine, says his group's latest work has two central findings. First, among the naturally occurring cannabinoid lipids thought to help reduce bodily movement, only anandamide release is stimulated by neural activity. Second, when cannabinoid receptors are blocked, followed an hour later by administration of a dopamine agonist, motor activity increases markedly over that of dopamine binding without a blockade of cannabinoid receptors. This indicates not only that the cannabinoid system interacts with dopamine in striatal signaling, but that anandamide works through a feedback mechanism to curb excess motor activity prompted by dopamine. "Most pharmaceutical companies, for lack of better options, look to improving existing dopamine antagonists," Piomelli notes. "Despite differences among all these [medical] conditions, the therapy is unfortunately quite basic." It also can be ineffective, and often has serious side effects. Drugs that enhance the natural antagonism of the cannabinoid system to dopamine would represent a new approach to taming neuropsychiatric ailments. Piomelli says his team is already at work on developing such compounds. --Steve Bunk

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Ricki Lewis

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April 1999

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