Survivin in 3-D
Scientists at the Salk Institute have deciphered the three-dimensional structure of survivin, the molecule that allows survival of cells that would normally undergo programmed cell death, apoptosis. (M.A. Verdecia et al., "Structure of the human anti-apoptosis protein survivin reveals a dimeric arrangement," Nature Structural Biology, 7:602-8, July 2000). Survivin is turned on in almost half the malignancies seen in the clinic--including breast, lung, prostate, and colon cancers, points out Salk associate professor Joseph P. Noel, senior author of the study. Having the first atomic resolution view of the protein--achieved through X-ray crystallography--and knowing the chemistry associated with the amino acids allow researchers "to make predictions about how survivin works, what it binds to, and maybe how to inhibit its function through structure-based drug design," Noel says. Survivin, discovered by Dario Altieri at Yale University (R. Wade et al., "Survivin, a novel anti-apoptosis gene, is expressed in the rat ovary," Biology of Reproduction, 60:407, Suppl. 1, 1999), is thought to attach to the "mitotic spindle," a foundation in the nucleus of cells that pulls newly divided chromosomes into the two daughter cells created during cell division. "Its three-dimensional structure suggests that it accomplishes this task by setting the stage for the assembly of this foundation. Tear down this foundation and the cell is unable to pull itself apart and dies," Noel explains. "Survivin binds to a number of proteins in the cell during mitosis, and these interactions are key elements of how survivin works. Some of these proteins are known, others not yet. In our laboratory, we hope to continue to characterize the structure of survivin when bound to these other proteins."
Tracking Melanoma Metastasis
If researchers could unravel the complex genetic underpinnings of cancer metastasis, better treatments and diagnostics would surely follow. Metastasis, the shedding of cancer cells from primary tumors and the cells' migration throughout the body, accounts for the vast majority of cancer deaths. Two recent studies demonstrate the power of microarrays, which facilitate the profiling of thousands of genes simultaneously, to explore melanoma metastasis. Researchers identified individual genes crucial to melanoma metastasis and groups of genes crucial for diagnosing the disease and assessing its potential to spread. In one study, researchers found that 31 of the 10,000 genes profiled had enhanced expression in metastatic melanoma cells (E.A. Clark et al., "Genomic analysis of metastasis reveals an essential role for RhoC," Nature, 406:532-5, Aug. 3, 2000). They singled out one overexpressed gene in particular--a cell movement and cytoskeletal regulator called RhoC--and demonstrated its essential role in tumor invasion through subsequent mouse studies; in so doing, they identified a possible treatment target. In an accompanying Nature study, researchers identified a subset of melanomas based on a mathematical analysis of gene expression (M. Bittner et al., "Molecular classification of cutaneous malignant melanoma by gene expression profiling," Nature, 406:536-40, Aug. 3, 2000). Such profiling should expedite the development of diagnostic metastasis tests based on primary tumor samples. "Then you could decide--do you have to be aggressive with treatment, or do you keep a watchful eye?" explains the first study's senior author, Richard O. Hynes, director of the Center for Cancer Research at the Massachusetts Institute of Technology. According to Hynes, the recent influx of genome information and a better understanding of cell movement and adhesion has made the complicated process of metastasis more accessible. Investigators plan to do more melanoma gene profiling as more mouse and human genes are annotated and identified.
Leptospirosis in Rice Farmers
Leptospirosis is a bacterial infection that causes high fever, chills, severe headache, and muscle aches, and it can progress to meningitis if not treated with antibiotics. The bacteria pass to humans in the urine of a variety of domesticated animals, including cattle, pigs, dogs, and horses, as well as rodents and other wild species, but it cannot pass from person to person. Those who come into contact with stagnant water are at risk--including farmers, sewage workers, military personnel, and people who wade, swim, or white-water raft in contaminated waters. At the second International Conference on Emerging Infectious Diseases 2000, held in Atlanta July 16-19, David Ashford, a veterinarian with the Center for Infectious Diseases, division of bacterial and mycotic diseases, at the Centers for Disease Control and Prevention, reported on a case-control study of an outbreak of leptospirosis that has plagued northern Thailand since 1996. Most of 62 ill individuals in the study were male rice farmers. "They plow fields in the rainy season, sow seeds during floods, allow one month of growth, and then transplant the sprouts to new flooded fields. Then they fertilize the fields and harvest the crop," explained Ashford. Because an outbreak in Barbados was linked to gardening and dog ownership, canine connections were examined in the Thailand group too, but they actually turned out to be seemingly protective. The rice farmers are most likely being infected by contact in the water with rodent urine. "The increase may reflect increased reporting due to both public health awareness and rapid diagnostic assays," said Ashford. A related concern is the current explosion of the rat population in New York City--rats arriving from Thailand could pose a problem.
USDA Developing Rapid Scrapie Test
Just as U.S. Department of Agriculture officials were removing sheep with a suspected transmissible spongiform encephalopathy (TSE) from a Vermont farm the week of July 17, researchers at the second International Conference on Emerging Infectious Diseases, held in Atlanta July 16-19, described a monoclonal antibody (MAb)-based diagnostic for the sheep disease scrapie in the works. Scrapie first entered U.S. flocks from Europe in 1947, and investigators have been trying to eradicate it ever since. Although scrapie is an ancient scourge and does not affect humans, the rise of variant Creutzfeldt-Jakob disease in European humans from eating beef from cows with bovine spongiform encephalopathy has increased attention to mammals harboring TSEs of any kind. Existing tests can take a year or more to nail down the precise TSE afflicting sheep. The new test is not only faster, but cheaper and easier to use. The brainchild of Katherine O'Rourke, a microbiologist at the animal disease research unit of the Agricultural Research Service in Pullman, Wash., and coworkers from Washington State University and Utah State University, the new test targets aberrant prions lurking in lymphoid tissue behind the "third eyelid," also known as the nictitating membrane. Tests on other lymphoid tissues require a general anesthetic, but the new test requires only a local. The MAb is linked to a reporter molecule that turns red when it binds the target. The antibody is two pronged and therefore specific enough to home in on the target, yet diverse enough to be useful on many varieties of sheep. The new test works early in the course of this slow infection. "The scrapie form of the prion protein appears in some lymphoid tissues nine to 14 months after infection, in the brain from 24 to 36 months, and then produces clinical signs at 36 to 48 months. The early accumulation in lymphoid tissue is the basis of the test. Every sheep with a positive eyelid test died three to 20 months later," O'Rourke said. The test will offer long-term advantages. Besides helping sheep farmers identify illnesses early on, it will enable the sheep industry to test all animals for genetic susceptibility to prion diseases. With culling, the entire U.S. sheep population will eventually be scrapie free. Similar efforts directed at bovines could someday guard against BSE.