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Above is a photomicrograph of the spinal cord terminal of a sensory axon. The neuron's immunoreactivity for human preproenkephalin suggests that the preproenkephalin gene, which was delivered via a herpes virus vector, is being expressed in sensory neurons. TELOMERE TROUBLES Lack of telomerase makes mice old before their time, a new study shows, but what effect this might have on age-related disease remains uncertain (K.L. Rudolph et al., "Longevity, stress, response, and cancer in aging telomerase-deficient mice," Cell, 96:701-12, March 5, 1999). Telomerase is a key enzyme in making telomeres, protective elements at the ends of chromosomes. Mice deficient in telomerase have shorter-than- normal telomeres that crumble when cells mature and divide, leading more quickly to cell senescence. The study indicates that knockout mice in generations bred for the shortest telomeres tend to develop tumors more often than normal, respond less well to wounds and loss of blood, and die sooner. However, their hearts, livers, kidneys, bones, and eyes remain normal. "Organs that have a low rate of cell turnover, like the brain and the heart, are not affected," notes lead author Karl Lenhard Rudolph, a research associate in medicine at the Dana-Farber Cancer Institute in Boston and Harvard Medical School. He adds that the hemopoietic system, hair, skin, and other body parts requiring high cell turnover do exhibit phenotypic changes from telomerase loss. "Our original idea was [to ask], can inhibition of telomerase and limitation of cellular proliferation limit cancer growth, because so many cancers have activated telomerase," Rudolph comments. "That's still an open question." He says the team's future work will focus on whether inactivation of telomerase in later life can slow cancerous growth, as well as studying the effects of telomere shortening on signaling and cell cycle regulation. --Steve Bunk INCREASING AFFINITIES Modulating the affinity of a small-molecule ligand to its target protein may help drug developers design more specific drugs. Researchers at Stanford University and the Howard Hughes Medical Institute created a bifunctional molecule by linking a ligand to a small molecule that binds tightly to a second protein. When they applied this strategy to an intractable target, the Sh2 domain, the researchers demonstrated a threefold enhancement over the natural peptide. "Nobody is suggesting this is going to replace or supplant traditional med-chem, but it is an additional tool in our toolbox to help us try to accomplish three things: improve the affinity of the molecule to its target protein; disrupt undesirable protein-protein interactions; and, potentially, improve the pharmacology of a particular compound," says coauthor Thomas J. Wandless, assistant professor of chemistry at Stanford University. George Whitesides, Harvard University professor of chemistry, comments that the finding represents a move beyond the site-specific, single-receptor model to a more complex view of molecular chemistry. But he remains uncertain how it will translate into the marketplace: "This is clearly an exquisite research tool and whether it will lead into ... practical pharmaceuticals is pretty hard to say at this stage." Next, the researchers plan to study the mechanism and boost the binding affinity even further. "We would like to see if we can improve the bindings by a factor of 100 or even 1,000," concludes Wandless. --A.J.S. Rayl YEAST GETS DRUGGED A blow has been struck against the old fear of good results in vitro, no luck in vivo, by a new way to test drugs and their possible targets directly on living organisms (G. Giaever et al., "Genomic profiling of drug sensitivities via induced haploinsufficiency," Nature Genetics, 21:278-83, March 1999). "We can dump a drug on yeast and ask the yeast to tell us what proteins are most affected by that drug," says lead author Guri Giaever, a research associate in Stanford University School of Medicine's biochemistry department. The team, headed by Stanford genetics professor Ron Davis, relies on the whole genome sequence of the yeast Saccharomyces cerevisiae and strains constructed by the international S. cerevisiae Deletion Consortium. Diploid yeasts carry two copies of every gene, as do humans. In the new process, one of the copies is deleted and each mutant strain is labeled with a molecular "bar code." Then the strains are mixed and grown in the presence of a nonlethal concentration of a drug. Most strains are unaffected, but a few are "haploinsufficient," the loss of their copy leading to an abnormal phenotype under the drug-induced stress. Subsequent undetectability of their bar codes due to growth inhibition suggests that the corresponding products of the deleted genes are targets for that drug. About half of the yeast's 6,000 genes have human homologues. So far, 233 mutant yeast strains have been profiled, revealing two drug- sensitive genes. Giaever expects the deletion project that enables continued drug-target identification to be completed in about 18 months. --Steve Bunk BIOTECH REPORT CARD The first-ever analysis of the impact of biotechnology on agriculture confirms what many had already assumed: Biotechnology is a good thing. The study, released on March 16 by the National Center for Food and Agriculture Policy (NCFAP), found that biotechnology products, which are currently used on over 50 million acres of cropland in the United States, have led to significant increases in crop yields, reductions in pesticides, and a shift to farming practices that promote integrated pest management and conservation tillage. "The fact that the technology is on so many acres of our cropland so quickly is going to have to be, should we say, accounted for," says Leonard Gianessi, the senior research associate at NCFAP who presented the report. "There's no getting around it. It's a done deal." Gianessi cites as an example of the positive impact of biotechnology the corn bore, a pest that many farmers didn't want to attack with pesticides; introducing biotechnology products translated into pest control and increased corn yields. The study, entitled "Impact of Biotechnology on U.S. Crop Production," is based on surveys from 1997 and 1998, studies from agriculture companies, and interviews with agriculture specialists including wheat scientists and entomologists. Gianessi guarantees future studies especially in light of new, potentially important wheat and rice crop products that are currently in the pipeline. --Eugene Russo Abnormal A-ß protein fragments accumulate in the characteristic senile plaques and tangles of Alzheimer's disease, pictured above. The round structure in the center is an amyloid plaque. Below it is a tangled nerve cell. SEARCHING FOR PATHOGENIC ROLE FOR AD RISK FACTOR ApolipoproteinE (apoE), and the apoE4 allele in particular, are proven risk factors for Alzheimer's disease (AD) in humans; beta amyloid (Aß), a deadly protein that accumulates in the brains of AD sufferers, has for some time been implicated in the onset of the disease. But although several studies have demonstrated a correlation between apoE4 and increased Aß accumulation in the brains of deceased AD patients, discovering whether apoE increases or decreases Aß deposition and by what mechanism has proven difficult. Researchers from Washington University in St. Louis and Lilly Research Laboratories in Indianapolis recently took an important step in elucidating this relationship by devising the first in vivo model to use transgenic mice that express human apoE (D.M. Holtzman et al., "Expression of human apolipoprotein E reduces amyloid-ß deposition in a mouse model of Alzheimer's disease," Journal of Clinical Investigation, 103:15-20, March 15, 1999). While a previous study by Lilly investigators had found that a lack of mouse apoE had reduced Aß deposition (K.R. Bales et al., "Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition," Nature Genetics, 17:263-4, 1997), the more recent paper found, to researchers' surprise, that human apoE had the opposite effect. According to lead author David M. Holtzman, an assistant professor of neurology and molecular biology at Washington University, preliminary data not included in the paper suggest two possible nonmutually exclusive reasons for the discrepancy: the first, that mouse apoE causes more A ß to become fibrillar than human apoE; the second, that the human apoE is simply better at clearing A ß . "If clearance is occurring, then you might expect that more apoE would be better," explains Holtzman, whose team continues to study the older animals. "But if ... apoE is simply causing Aß to become fibrillar, then more apoE may be bad." --Eugene Russo Steven Wilson HUMAN TRANSGENE RELIEVES PAIN IN MICE Herpes simplex I is a promising vector in several gene therapies because it hides in sensory neurons, turning off its own genes, but expressing transgenes. Steven Wilson, a professor of pharmacology and physiology at the University of South Carolina in Columbia and collaborators at the University of Pittsburgh and University of Illinois at Chicago have equipped the virus with a human gene encoding the natural painkiller preproenkephalin (S.P. Wilson et al., "Antihyperalgesic effects of infection with a preproenkephalin-encoding herpes virus," Proceedings of the National Academy of Sciences, 96:3211-6, March 16, 1999). "There is no treatment for chronic pain, such as from shingles, phantom limb syndrome, osteoarthritis, and cancer--that's millions of people," says Joseph Glorioso, director of the human gene therapy center at the University of Pittsburgh and part of the team. The researchers developed a rodent model of chronic pain--rubbing the hindpaw with capsaicin (the "hot" in red hot chili peppers) before applying heat. Mice given a control sham virus rapidly withdrew the hot paw, but mice given the enkephalin-carrying virus were considerably slower to withdraw the paw, or didn't do so at all. Notably, the groups didn't differ when capsaicin wasn't given. "In contrast to current pain control methods, the gene-vector based therapy is highly localized, and the release of the potentially pain-relieving substance is self-limiting because it is triggered only when the nerves encounter hyperstimulation," says Wilson. Adds Glorioso, "It would work like morphine, but applied locally, and without the downside of addiction."--Ricki Lewis U.S. AND FRANCE DIFFER IN BREAST CANCER APPROACHES Cultural differences between the U.S. and France may explain why recent recommendations to prevent breast cancer differ on three key measures where efficacy is not known, report researchers from the Paoli-Calmetres Institute in Marseilles and the Johns Hopkins Medical Institutions (F. Eisinger et al., "Cultural basis for differences between U.S. and French clinical recommendations for women at increased risk of breast and ovarian cancer," The Lancet, 353:919-20, March 13, 1999). Whereas American women are taught to perform monthly breast self-exams to detect tumors, in France physicians do it, partly because self-exam "may induce anxiety in some women" (F. Eisinger et al., "Recommendations for medical management of hereditary breast and ovarian cancer: The French National Ad Hoc Committee," Annals of Oncology, 9:939-50, September 1998). U.S. but not French doctors tell women to exercise, not smoke, and eat a low-fat diet to lower risk of breast cancer. The approaches differ most in criteria for removal of breasts and/or ovaries to prevent cancer. In the United States, this is done following informed consent from a woman, who typically has a very strong family history of the disease or knows she has inherited a breast cancer gene. The French spell out restrictions, advising doctors to "oppose" prophylactic mastectomy in women under 30 and oophorectomy in women under 35, and consider these procedures only if cancer risk exceeds 60 percent and 20 percent, respectively. In France, "it's not enough to simply ask for the procedure. More importantly, it wouldn't be suggested, as it would be here," says Gail Geller, an associate professor of pediatrics in the school of medicine at Hopkins and coauthor of the Lancet paper. The French conservatism, the researchers conclude, is consistent with their paternalistic health care system, but it may also reflect greater distaste at the "mutilation" of breasts, and concern over France's low birth rate. "We hypothesize that a significant part of the difference is due to cultural attitudes. In the [United States], instructing women in breast self-exam fits into our cultural value system of controlling our own health care. In France, it doesn't fit the cultural value system that reveres the aesthetic and sensual value of breasts," Geller adds. --Ricki Lewis

Notebook

Mar 28, 1999

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