Research Notes

Putting Polio to Good Use Add polio to a host of other viral and bacterial foes that, in modified forms, could prove therapeutically beneficial. Although Russian scientists attempted to use polio to treat cancer in the 1960s--unpublished experiments about which little is known--a recent brain cancer study in mice is the first modern-day attempt to harness the power of the virus (M. Gromeier et al., "Intergeneric poliovirus recombinants for the treatment of malignant glioma," Proceedings of the National Academy of Sciences, 97:6803-8, June 6, 2000). Study investigators report that polio, a skilled neural pathogen, may be particularly suitable for destroying malignant gliomas, cancers typically difficult to target with chemotherapy or radiation because of the brain's nearly impenetrable defenses. In one series of experiments, 18 of 25 mice with brain tumors had no evidence of residual tumors after injection with the virus. Aiding polio's potency and specificity is the virus' affinity for the CD155 receptor, a molecule that many brain tumor cells express, though normal glial cells do not. And as a rapidly growing, cell-busting lytic virus, polio works quickly, efficiently, and without inducing latency. "It's a self-limited infection that resolves by itself without persisting," explains the study's lead author, Matthias Gromeier, now an assistant professor of microbiology at Duke University. To disable the poliovirus' ability to cause neurologic disease, investigators constructed a chimera of poliovirus and human rhinovirus type 2, called PV1(RIPO). According to Gromeier, it's unclear how the World Health Organization's planned worldwide eradication of polio might affect research like his group's. "This is a very, very specialized treatment that could conceivably be conducted in a specialized center," says Gromeier, noting that PV1(RIPO) is as harmless as polio vaccines themselves. He and his colleagues are now preparing to apply for Phase I trials. "There is a general sense of urgency because malignant gliomas are resistant to just about any kind of treatment and are invariably fatal," comments Gromeier. --Eugene Russo Drosophila Knockout Fruit fly geneticists, despite their myriad accomplishments, have for years been at a technical disadvantage. Deprived of the gene function-erasing "knockout" techniques that have been invaluable in elucidating gene function in mice and yeast, fly geneticists have been confined to often-laborious crossbreeding experiments. Now, University of Utah researchers report the development of a new method that not only arms fly geneticists with knockout- and mutation-rescuing power, but also could enable scientists to access the genetic secrets of genetically nonviable but important animal models such as mosquitoes (Y.S. Rong, K.G. Golic, "Gene targeting by homologous recombination in Drosophila," Science, 288:2013-8, June 16, 2000). Investigators based their technique on the observed recombination mechanics of yeast: If a cloned yeast gene is cut with a restriction enzyme and placed in a single yeast cell, it will find and recombine with the homologous gene, allowing for future genetically altered generations. But manipulation of single cells in the multicellular fruit fly isn't feasible, and unlike mice, there's no cell culture system for introducing genes into embryonic stem cells in vitro. The Utah researchers had to use special yeast enzymes to precisely deliver their target gene in young fruit flies, have it recombine with the homologous gene, and have its associated trait expressed in the next generation. According to senior author Kent G. Golic, a professor of biology at Utah, the method could shave months, even years, off mutation generation in flies, thereby facilitating the study of more than 10,000 fly genes whose functions remain unknown. He and his colleagues intend to make the technique faster and more efficient. "We think that probably it'll also work in other organisms," says Golic, specifically citing plants and the mosquito. "There's nothing fly-specific about what we've done." --Eugene Russo Risky Immortalization? Telomerase, an enzyme that allows cells to divide indefinitely, has caught the attention of many scientists who hope to harness its ability to immortalize cells for tissue engineering. So far researchers have been fairly confident that they can propagate cells beyond their natural lifetimes without introducing oncogenic mutations. However, David Beach, professor of biology at University College, London, and colleagues caution scientists about using cells immortalized with telomerase for therapeutic purposes. They found that telomerase-driven cell proliferation is associated with c-MYC oncogene activation in human mammary epithelial cells (HMEC) (J. Wang et al., "Risky immortalization by telomerase," Nature, 405:755-6, June 15, 2000). The researchers used a retrovirus to incorporate hTERT, the catalytic subunit of telomerase, into HMEC cultures. After 150 population doublings, they excised hTERT using Cre recombinase. To their surprise, telomerase activity remained high and the cells continued to grow without the exogenous telomerase. Prompted by past results, they determined that up-regulation of c-MYC somehow turned on the cells' own telomerase production, but the researchers didn't elaborate further. The authors also note that the chromosome number in the HMEC cells remains normal, which seems doubtful to some telomerase researchers. Jerry Shay, professor of cell biology at the University of Texas Southwestern Medical Center, who did some of the original work on telomerase, points out a key difference between the current work and earlier studies: "The culture conditions for HMEC select for cells that don't have p16, an important cell cycle checkpoint. The p16 pathway is still intact in the cells that our group and others have studied." Shay will be publishing results showing that removal of exogenous telomerase from fibroblast cells results in eventual telomere shortening and senescence. He adds that cells overexpressing c-MYC and telomerase in the present study may not be cancerous. The question of whether the finding from the Nature paper can be generalized to other cells remains to be determined. --Nadia S. Halim Academic Market Opens for Celera After lengthy discussions that started last year, Vanderbilt University, Nashville, Tenn., subscribed to Celera Genomics' databases last month, becoming the first academic institution to do so. The five-year subscription gives Vanderbilt researchers access to the Celera Human Gene Index, which provides a set of genes derived from expressed sequence tag (EST) sequencing programs, and the Human Genome Database with links to genes and their associated biological information. They will also have access to the Drosophila Genome Database, the Mouse Genome Database, and single nucleotide polymorphism (SNP) data. Because Celera previously dealt solely with pharmaceutical companies, Vanderbilt needed to create a model that would be amenable to the academic environment and compatible with the Celera business model. According to Mark Magnuson, assistant vice chancellor for research at Vanderbilt University, Vanderbilt insisted on unrestricted rights to publish any research developed from information contained in the databases. Vanderbilt will also retain ownership of intellectual property rights that come from the use of Celera's databases. "Of course, we don't have absolutely free rights to do anything we please," says Magnuson. The core issue for Celera and the point that Vanderbilt conceded on: the ability to reproduce the databases. Some researchers think this is a big restriction because they won't be able to copy parts of the databases and customize them for individual use. "Overall we are pleased with how this has evolved. We think that our contract provides workable solutions to the key issues that academic institutions face," comments Magnuson. He adds that universities have called to discuss the terms for the agreement and found them acceptable. --Nadia S. Halim

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Eugene Russo

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June 2000

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