Notebook

Worse Than Expected Under New Management How They're Hooked On Target Royal Tribute To Science FDA Approves Obesity Drug Gene Lawsuit On January 1, Brookhaven Science Associates (BSA), a nonprofit partnership of the State University of New York, Stony Brook, and Columbus, Ohio-based Battelle Memorial Research Institute, assumed operation of the Department of Energy's (DOE's) Brookhaven National Laboratory in Upton, N.Y. The yearly management fee for the five-year, $2 billion contract will be $5.3 million, up from the 1997 fee of $3.8 million paid to the lab's former operator, Associated Universities Inc. That company lost the contract last May after the discovery that water contaminated with tritium had been leeching into the area's groundwater for years (Notebook, The Scientist, March 31, 1997, page 23). Brookhaven's new director, John Marburger, says the extra cost will help ensure the lab's safety. "We believe this lab can be operated in a perfectly clean fashion," he maintains. The new contractor must convince both Congress, which has been critical of DOE's handling of the Brookhaven affair, and neighbors who live near the lab that the tritium spill can be cleaned up and the lab run without further mishap. Marburger says that although the lab's existing employees will be retained, many jobs could be reassigned, since BSA will provide its own people to fill the top seven management positions. Marburger also states that the High Flux Beam Reactor, whose spent fuel pool caused the tritium leak, will remain shut down until at least 1999. The spread of AIDS may be double the rate previously thought, according to new estimates. For 1996, the United Nations (U.N.) estimated that HIV was being transmitted at a rate of 8,200 new infections a day. For 1997, the U.N. boosted the rate to 16,000. The tally of global AIDS cases was also revised from 22.6 million in 1996 to 30.6 million in 1997. Although the increases may be due to a hastening spread of the virus, the changes also may be due, in part, to a change in the way the U.N. scientists model the spread of the virus. Models through 1996 looked at regions, while the 1997 estimates are based on models with more specific country-by-country data. The old technique resulted in underrepresentation of HIV transmissions in sub-Saharan Africa, the region with the greatest concentration of HIV infection. "It now appears that previous calculations grossly underestimated the rate of transmission," according to the Report on the Global HIV/AIDS Epidemic, released in December as a joint effort of the United Nations Programme on HIV/AIDS and the World Health Organization. Since many countries in the region had few data, U.N. scientists used Uganda, which had better HIV reporting, as the baseline for the region. However, as more data from other countries have become available, Uganda does not appear to be representative of the entire region. Adjusting for previous underestimates, there have been about 9 percent more new infections in 1997 and the number of people living with HIV has increased 13 percent. The report also emphasizes the rift in HIV transmission between the industrialized world and developing nations. In 1996, the number of new AIDS cases decreased in the United States and Europe, while cases in developing nations, particularly sub-Saharan Africa, have climbed. THE LURE: Chronic smokers tolerate and crave nicotine because of its effects on acetylcholine receptors, says Penn's Jon Lindstrom. Researchers are discovering how chronic use of nicotine enables smokers to tolerate otherwise toxic amounts of the drug, while keeping the craving alive. At the University of Pennsylvania Medical Center, a team led by Jon Lindstrom, a professor of neuroscience, reported that chronic exposure to levels of nicotine typical of that found in a smoker's blood exerts different effects on human receptor subtypes for acetylcholine, a neurotransmitter vital to autonomic and neuromuscular functions that also plays important but less well-characterized roles in the brain. Nicotine can activate acetylcholine receptors (AChRs) when applied to them for a few milliseconds or seconds. The study results, published in November (F. Olale et al., Journal of Pharmacology and Experimental Therapeutics, 283 :675-83, 1997), show that alpha-7 and alpha-4-beta-2, the two most numerous AChRs in the brain, are often permanently inactivated by chronic exposure to nicotine. This could explain a smoker's high tolerance for nicotine. An AChR subtype much less plentiful in the brain than the other two, alpha-3, was found to remain capable of activation. This could account for continued craving, in that AChRs are known to facilitate the release of dopamine, a neurotransmitter involved in the reward system of many addictive drugs. Lindstrom notes, "The $64,000 question in all this is, which AChR subtypes in which pathways regulate which physiological reactions?" Among the varying individual reactions to nicotine are heightened attention and suppression of anxiety, appetite, and pain, as well as elevated blood pressure and heart rate. Several pharmaceutical companies already are working on subtype-specific nicotine agonists that could help to treat neurological disorders such as Alzheimer's disease and Parkinson's disease. In gene therapy, when the therapeutic gene is carried by a viral vector it enters the chromosome at random. Depending on where the new gene ends up, it could function poorly or not at all, and could damage neighboring DNA. What's needed is site-specific targeting. Recent research suggests that the parvovirus family could be the vectors to do that job. A team led by Ernest Winocour, a professor of molecular genetics at the Weizmann Institute of Science in Rehovot, Israel, has established how a type of parvovirus called the minute virus of mice (MVM) inserts itself into a specific location in the chromosome. The study, published in December (J. Corsini et al., Journal of Virology, 71 :9008-15, 1997), follows an earlier collaboration between Winocour's group and scientists at Cornell University Medical College that identified a similar targeting mechanism of another parvovirus, called adeno-associated virus (AAV). "There were grounds for assuming that the single site-specific chromosomal insertion was a peculiarity of AAV," Winocour notes. In the two parvoviruses, replicator proteins are thought to bind to recognition sequences in both the viral and the chromosomal DNA, thereby "gluing" the incoming viral DNA to a specific location in the chromosome. There are about 50 known parvoviruses, each of which might be capable of such targeting. "It is our goal that in the future, a collection of parvovirus vectors will allow the scientist to insert a therapeutic gene at a number of different chromosomal positions," says Winocour. ADVANCES THROUGH SCIENCE: Former Merck CEO P. Roy Vagelos, left, and Johns Hopkins' Alfred Sommer will receive the Prince Mahidol Awards Thailand's 1998 Prince Mahidol Awards will honor four researchers for their outstanding contributions to society through science on January 28. Alfred Sommer, dean of the Johns Hopkins College of Public Health and Hygiene, and Guillermo Arroyave, a San Diego-based researcher with the Institute of Nutrition of Central America and Panama, will share an award for their work in understanding and eradicating vitamin A deficiency. Sastoshi Omura, president of the Kitasato Institute in Tokyo, and P. Roy Vagelos, chairman of the board of trustees at the University of Pennsylvania and retired CEO of Whitehouse Station, N.J.-based Merck and Co. Inc., will share a prize for the discovery of the antibiotic cerulenin, also known as ivermectin. In 1973, Omura and Vagelos isolated and defined the action of ivermectin (G. D'Agnolo et al., Biochimica et Biophysica Acta, 326 [2]:155-6, 1973). The antibiotic has been widely used in treating onchocerciasis, or river blindness. Under the leadership of Vagelos, Merck has played a major role in controlling the spread of onchocerciasis, the second leading cause of blindness in the world, through its donation of more than $80 million worth of ivermectin to the World Health Organization (WHO). Sommer will be honored for his research showing that supplementing children's diets with low-doses of vitamin A can help prevent death from diseases as well as blindness. The winner of the 1997 Lasker Clinical Research Award, Sommer has earned a reputation for his tireless campaign to make the eradication of vitamin A deficiency a top priority of WHO and the United Nations International Children's Emergency Fund, according to Joseph L. Goldstein, chairman of the Lasker Awards jury (S.P. Hoffert, The Scientist, Oct. 27, 1997, page 1). Arroyave also was cited for his leadership in the war on vitamin A deficiency. Foods fortified with vitamin A like butter and milk typically are unavailable to high-risk populations. Arroyave's research led to legislation mandating the supplementation of sugar in Costa Rica, Guatemala, Honduras, and Panama. The awards were created in 1992 to honor Thailand's King Bhumibol's father, Prince Mahidol, who is regarded as the founder of modern medicine and public health in Thailand. Nomination forms can be obtained from the Prince Mahidol Foundation Prive Repository at Suite 115-Mail Stop 174, 1230 York Ave., New York, N.Y., 10021-6399. CRAVING DRUG: Knoll Pharmaceuticals won FDA approval for Meridia, a reuptake inhibitor that can help to control appetite craving. On November 24, Knoll Pharmaceutical Co., based in Mount Olive, N.J., won approval from the United States Food and Drug Administration (FDA) to market the new obesity drug Meridia (sibutramine hydrochloride monohydrate). Unlike other obesity drugs on the market, Meridia does not enter cells to boost the release of serotonin, which controls appetite craving and the body's feeling of fullness after eating. Instead, Meridia works as a reuptake inhibitor by slowing the reabsorption of serotonin and prolonging the suppression of appetite. Other reuptake inhibitors on the market include the antidepressant Prozac. Meridia, however, is the first reuptake inhibitor to be used for treating obesity, according to Timothy B. Seaton, Knoll's senior medical researcher for endocrinology and metabolism. "Ironically, Meridia was originally developed as an antidepressant by our laboratories," Seaton says. "Clinical trials soon showed it was ineffective for this purpose. But we observed weight loss in patients and soon thought of it as a promising obesity drug." In clinical trials involving more than 6,000 patients, Meridia produced 5 percent to 10 percent weight loss in almost all participants. FDA had been concerned about the drug's tendency to increase blood pressure in some patients. Studies by Knoll indicate this typically occurs early in treatment and lower doses can improve the situation, according to Seaton. Myriad Genetics Inc., based in Salt Lake City, Utah, is suing a rival company for infringement on its patent for searching for certain mutations on the breast cancer gene BRCA1. Myriad, which was awarded a patent on December 2 for diagnostic methods covering 47 mutations on BRCA1, filed suit on the same day against Gaithersburg, Md.-based Oncormed Inc. Among the mutations covered by the Myriad patent are two found in more than 1 percent of women of Ashkenazi (Eastern European) Jewish descent. The mutations are thought to account for higher breast and ovarian cancer rates within the group in the United States (D. Shattuck-Eidens et al., JAMA-Journal of the American Medical Association, 278 [15]:1242-50, 1997). In the lawsuit, Oncormed diagnostic tests are claimed to overlap with those developed by Myriad. Under U.S. patent law, a research organization may patent genetic tests developed to detect diseases associated with certain mutations. In November, Oncormed filed a similar lawsuit against Myriad for infringement on its own tests for certain mutations BRCA1.

Notebook

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January 1998

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