RNA vaccine

A new twist on genetic immunization has beenreported by researchers at the University ofVienna, Austria. Until recently, most geneticvaccines under development have been basedon DNA; however, in a recent report (Nat. Med.4:1438, 1998), Christian Mandl and his col-leagues have demonstrated the efficacy of anRNA-based vaccine. They showed that miceinoculated with an RNA vaccine developedfrom the virus that causes tick borne encephali-tis (TBE) survive subsequent infection withwild-type TBE virus. After in vitro synthesis ofTBE genomic RNA in Escherichia coli, the RNAwas purified, used to coat gold beads, and inoc-ulated into mice using a gene gun. According tothe authors, only 0.1 ng of RNA was sufficientfor an infectious dose. In contrast, an attenuat-ed form of the virus created by mutations in anoncoding region of the virus was able to con-fer protection against live virus at a dose of 5 ngof RNA. In the future, vaccine developers willhave to grapple with the thorny issue ofwhether DNA or RNA is the better vaccine can-didate: “Using RNA, you eliminate some of theconcern for potential DNA integration,” saysMargaret Liu, vice president of vaccine devel-opment at Chiron Corporation (Emeryville,CA), “However, there is a possibility of rever-sion with RNA vaccines.”

Oocyte gene transfer

Taking advantage of what may be an evolu-tionarily conserved “back door” to genomicmodification, researchers at Gala Design(Sauk City, WI), the University of Wisconsin,Madison, and the University of California, SanDiego have developed a technique that mayhave extensive applications in generatingtransgenic animals. During the MII meioticarrest in oocyte development, the nuclearenvelope breaks down. Reasoning that thisevent would allow access to the genome, thescientists infected bovine MII oocytes with apseudotyped recombinant retrovirus carryinga reporter gene. The virus integrated efficient-ly, and, as the team reports in the NovemberPNAS (95:14028, 1998), embryos derivedfrom the infected oocytes carried the gene inall cells. Robert Bremel, managing director ofGala Design and senior author on the work,argues that the permeability of arrestedoocytes to gene insertion may have played arole in mammalian evolution, allowing natu-rally occurring retroviruses or transposons todeliver useful traits: “Operating repeatedlythrough many generations, this system wouldprovide a mechanism for periodic, dramaticquantum changes in phenotype.” Bremel addsthat the pseudotyped retrovirus allowsresearchers to take control of this process for abroad range of species, since “these vectors arevirtually universal gene transfer entities.” Thecompany plans to focus initially on expressingnovel proteins in transgenic cows’ milk.

NATURE BIOTECHNOLOGY VOL 17 JANUARY 1999 http://biotech.nature.com 9

IN BRIEF

RESEARCH NEWS

Efforts to elucidate an important develop-mental signaling pathway have opened thedoor to a broad range ofbiotechnology applica-tions—and generated anextremely hairy mouse. Themouse, which expresses atruncated, constitutivelyactive form of the beta-catenin signaling protein inits skin cells, generates newhair follicles as an adult.Ordinarily, new follicle for-mation stops before birth.While the discovery, report-ed in the November 25 issueof Cell (95:605), receivedextensive popular coverageas a potential cure for bald-ness, the researchers emphasize that sub-stantial barriers remain to such an applica-tion. “Whether such technology would beadvantageous in a clinical setting would be

dependent upon whether animal skin couldbe induced to make hair follicles without

progressing to skin tumors,”explains Elaine Fuchs, aprofessor in the HowardHughes Medical Institute atthe University of Chicagoand senior author on thestudy. While the tumorsappear late in the animal’slife and are relativelybenign, they are potentiallydisfiguring. Fuchs suggeststhat a more imminentapplication might be theproduction of transgenicsheep which yield morewool. The team is currentlytrying to develop a more

detailed model of the signaling pathway,which may also be involved in the develop-ment of teeth, nails, mammary glands, andother structures.

Silencing gene silence

Plant biotechnologists have a love-hate rela-tionship with the phenomenon known asposttranscriptional gene silencing (PTGS), amechanism by which plant cells shut downthe expression of highly abundant tran-scripts. PTGS appears to have evolved as adefense against viruses, raising the possibili-ty that plants could be “immunized” withviral transgenes. At the same time, the phe-nomenon often prevents high-level expres-sion of desirable transgenes. Now,researchers at Washington State University(Pullman, WA) report in the November 13issue of Cell (95:461, 1998) the discovery of aviral protein that shuts off PTGS. Cellsexpressing the P1/HC-Pro gene from tobac-co etch virus permit high-level expression ofa reporter gene that would ordinarily besilenced. While the viral gene would presum-ably facilitate the expression of transgenes inplants, James Carrington, a professor in theInstitute of Biological Chemistry atWashington State and senior author on thestudy, warns that silencing is still a double-edged sword: “A shutdown of gene silencingwould likely enhance susceptibility to mostviruses. This could potentially be a problemin large-scale outdoor field releases.”Nonetheless, several companies are explor-ing the possibility of using P1/HC-Pro tosuppress PTGS, and Carrington hopes thatthe finding will aid in uncovering the under-lying mechanism of the phenomenon.

Plant polyketides

Using reverse genetics and biochemistry, aGerman—Finnish collaboration headed byJoachim Shroeder and Teemu Teeri haveunmasked a role for a member of the chalconesynthase (CHS) family, gchs2 which suggeststhat CHS-related enzymes are involved in thebiosynthesis of a much larger range of plantproducts than previously realized (Nature396:387, 1998). The CHS superfamily synthe-sizes pyrones by using various substrates in athree-step condensation reaction of thepolyketide pathway. Deploying an antisenseversion of a cDNA from a CHS-like proteinfrom the ornamental plant Gerbera hybrida,the team was able to phenocopy a null muta-tion in gchs2. They then used nuclear magnet-ic resonance and mass spectroscopy to com-pare products of secondary metabolic path-ways in wild type and “mutant” plants, identi-fying two compounds whose biosynthesis wasnot known to originate from the polyketidepathway. What’s more, these compounds haveknown biological activities—they conferinsect and pathogen resistance.

Signal transduction gets hairy

Research News Briefs written by Alan Dove,Margret Einarson, and Musa M. Mhlanga

© 1999 Nature America Inc. • http://biotech.nature.com©

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