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Contents Human cells grow in rat brains Tumor-busting bugs Mice carrying elephants? Transgenic Arabidopsis In utero gene therapy advances John Critser HUMAN CELLS GROW IN RAT BRAINS A new in vivo model promises to shed light on how neural precursor cells migrate and take up residence in certain brain areas, with a little help from rats (O. Brustle et al., Nature Biotechnology, 16:1040-4, November 1998). Ronald McKay's group at the National Institute of Neurological Disorders and Stroke and Oliver Brustle's group at the University of Bonn Medical Center transplanted cells from human embryos into the ventricles of rat brains. The human cells migrated throughout the brain, and differentiated into the three major neural cell types, with no obvious effects on the host rodents. "The transplanted human cells incorporated individually into the developing rat brain, intermingling smoothly but not compressing the rat tissue," says Brustle, research group leader in the department of neuropathology. Human glial cells even wrapped around rat axons. The experiment may yield both basic and applied applications: "This will give us the opportunity to study the migration and differentiation of human neural precursor cells in a live nervous system. Another attractive application is the in vivo analysis of neural cells derived from patients with neurological diseases, to help delineate the target population of the disease process and to assay the effect of pharmaceutical agents on the affected human cells in vivo," Brustle says. And because the human cells occupied large areas beneath the ventricles, which are a lifelong storehouse of neural precursors, the research suggests a new route to developing cell-replacement strategies, he adds. TUMOR-BUSTING BUGS Injecting an attenuated adenovirus, then giving patients a dose of chemotherapy, shrinks head and neck tumors faster than either treatment alone, Frank McCormick reported at a November New York Academy of Sciences cancer conference. The University of California at San Francisco cancer researcher showed before-and-after slides of patients with baseball-size tumors that diminished drastically within four weeks of treatment. "What is the basis for this?" McCormick asked rhetorically during his presentation. The treatment works, in part, McCormick suspects, because the vaccine has been engineered to kill tumor cells deficient in p53 (P. Smaglik, The Scientist, 12[6]:1, March 16, 1998). However, he hypothesized further that the combination therapy somehow triggers the body's immune response, perhaps by unleashing TNFalpha and other cytokines. Complete Phase II data, unavailable at press time, will be announced Nov. 21 at the Gene Therapy for Cancer meeting in San Diego. Another group also has explored how viruses and the immune system may be able to shrink tumors. A team led by Patrick W.W. Lee, an oncologist at the University of Calgary Health Sciences Centre, used a different virus in different tumor types, but to similar effects in preclinical experiments. Their experiments employed a reovirus to interfere with the Ras signaling pathway, which is mutated in about 30 percent of human tumors. The group also explored the role of the immune system in cancer by injecting the reovirus into human and mouse tumor cells implanted in mice. Tumors in mice with deficient immune systems shrank more significantly, and with smaller doses, than tumors in mice with fully functioning immune systems (M.C. Coffey et al., Science, 282:1332-4, Nov. 13, 1998). MICE CARRYING ELEPHANTS? Elephants and mice usually don't get along, so goes the cliché. But a recent study (K. Gunasena, Animal Reproduction Science, 53:265-75, Oct. 30, 1998) suggests that elephants--African elephants in particular--as well as other endangered animals, may one day have smaller mammals such as mice to thank for the preservation of their entire species. While collecting elephant sperm in Africa as part of an ongoing elephant artificial insemination program at the Indianapolis Zoo, Purdue University scientists, working with researchers from the Advanced Fertility Institute at the Methodist Hospital of Indianapolis, decided to take advantage of their access to the largest living land mammal by c ollecting specimens for a separate experiment. They harvested elephant ovarian tissue, froze it, took it back to Indiana, and transplanted it into mice. To their delight, temporary surrogate mouse moms successfully generated ovarian follicles containing oocytes, or female gametes. Many scientists have proposed the development of so-called genome resource banks or reproductive tissue banks for endangered species. Genetic material could be preserved by freezing it and later using it in captive breeding programs to maintain species' genetic diversity. Collecting and freezing sperm is relatively easy; oocytes are a different story--hence ovarian tissue transfer. Although ovarian tissue transfer has been around since the 1950s, for years, it got little attention from scientists. A recent revival in the field has led to successful transplantations within (for example, mouse to mouse) and between (for example, mouse to sheep) species (K. Gunasena et al., Biology of Reproduction, 57:226-31, 1997). The latest report, however, "was important because it was the first demonstration that this procedure could be used for endangered species," says senior author John Critser, scientific director of the Cryobiology Research Institute, a division of both Purdue and Indiana Universities. The next step would be to transfer the eggs back into elephant moms who could then carry the youngsters to term. But a great deal of research remains to be done. Investigators still don't know if the elephant eggs produced were viable. Critser and his colleagues plan to follow up their study by "taking a step back" and working with a simpler, rat model system. He acknowledges that the procedure's still a long shot, but he notes that he recently received some welcome encouragement from a milestone at the Indianapolis Zoo: the first successful pregnancy by artificial insemination in an African elephant. He expects that some of the techniques used for that procedure would be similar to those necessary for ovary transfer. TRANSGENIC ARABIDOPSIS MEASURES CHERNOBYL RADIATION Transgenic Arabidopsis thaliana joins dead pines, mangled wheat chromosomes, and mutations in barn swallows as "bioindicators" of lingering radiation at the Chernobyl Nuclear Power Plant. Barbara Hohn, a professor at the Chernobyl Scientific and Technical Center of International Research, and coworkers created plants that carry a doctored gene for beta- glucuronidase (I. Kovalchuk et al., Nature Biotechnology, 16:1054-9, November 1998). The gene is in two sections, inverted with respect to each other, that have a region of sequence overlap, rendering it nonfunctional. When a mutation swaps the redundant areas, a functional transgene results. "On histochemical staining ... cells expressing ß-glucuronidase, and their progeny, could be precisely localized as blue sectors on white plants," says postdoctoral researcher Olga Kovalchuk. They grew plants in the field and in the lab in soil from seven areas within the 600-square-kilometer "exclusion zone" where agriculture is prohibited. Blue patches indicated a significantly hiked mutation rate at low to moderate radiation exposure, but not in the most contaminated "Red Forest," suggesting toxic, rather than mutagenic, effects there. The technique should find applications in other disaster areas. "It is quite easy to do. Normally, you'd have to analyze chromosomes, which means hundreds of hours of microscope work," comments Yuri Dubrova, a Wellcome Trust Research Fellow in the department of genetics at the University of Leicester, England, who wrote an article accompanying the report (Y. Dubrova, Nature Biotechnology 16:1010-1, November 1998). W. French Anderson IN UTERO GENE THERAPY ADVANCES Although pre-protocols for in utero gene therapy acted as a lightning rod for controversy when they were presented at a National Institutes of Health advisory committee meeting earlier this fall, animal experiments that will address some of those concerns will begin soon. W. French Anderson, gene therapy researcher at the University of Southern California at Los Angeles, who helped draft the protocols, remarked in a telephone interview that the biggest technical issue raised at the Recombinant DNA Advisory Committee (RAC) Sept. 23-24 was the potential for transplanted genes to end up in sperm and egg cells. The committee will closely monitor the progress of experiments in mice, sheep, and monkeys. "If we cannot reduce the potential of germ line gene transfer to a minimally accepted level, we will not proceed." Anderson notes. Because of separate ethical implications raised by treating an unborn fetus, the protocol thus far has been shaped by a panel of 26 reviewers, "scientists, ethicists, legal people, theologians, clinicians, and so on," Anderson notes. The experiments will feature retroviral vectors with all the viral regulatory sequences deleted, meaning that the therapeutic genes should, in theory, be controlled by human genomic regulatory sequences. Anderson expects in utero experiments in mice to begin soon. He will report back to the RAC Jan. 8-9.

Notebook

The Scientist Staff

Nov 22, 1998

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