Biolistic technology was originally developed in the area of plant genetics to introduce genes into target cells that were largely refractory to traditional methods of gene delivery (1). Biolistic lore holds that the gene gun was inspired by interactions between edible bonsai plants and squirrels, and the later involvement of an air rifle to control these interactions. Legend has it that in the course of those events, Dr. John Sanford made the pivotal extrapolation that if an air rifle could be used to deliver macrobullets into a macrotarget, perhaps another gun could be used to deliver microbullets into microtargets like living cells. By extension, if a microbullet could be shot into living cells without killing them, could a microbullet also be used to carry nucleic acids into those cells to genetically modify them?
The obvious answer now to this strikingly simple but powerful question is, of course, ''yes.'' However, moving from concept to a practical device that could deliver DNA into cells without killing them required a number of years of work by Sanford's group and several other groups. Sanford's group originally focused on biolistic gene delivery for plant and pro-karyotic applications (1,3,4). These efforts developed a wide variety of gene guns, including the precursor to the gunpowder-driven commercially available gene gun from BioRad. Further gene gun development occurred as a collaboration between John Sanford and Stephen Johnston, who did their graduate training together in Bob Hanneman's laboratory at
the University of Wisconsin. This collaboration between San-ford's group and Johnston's group enabled a number of new gene guns, including a helium-driven vacuum chamber device (Fig. 2A) that was the predecessor of BioRad's helium-driven PDS1000® for mammalian cell and animal transfection. This collaboration along with Rumsey-Loomis generated several handheld helium-driven guns (Fig. 2B) for animal transfection including the infamous ''bazooka'' and the ''wand'' (Fig. 3). The long-standing Sanford-Johnston collaboration also provided first demonstration of mitochondrial transformation by biolistics, as well as early demonstrations of transfection of mammalian cells and living animals in collaboration with Sandy Williams (5-7).
Following Sanford's first demonstration of gene gun technology (1), several other groups developed parallel or alternate gene gun technologies for biolistic gene delivery [reviewed in (7)]. Most notable of these are the efforts by the group from Agracetus (now Powderject), who developed a series of gene guns, including the electrically driven Accell® device (8), and an entrainment gene gun (Fig. 2C) that was the ultimate prototype for the commercially available Helios® device (BioRad).
Commercialization of the Helios gene gun was an important milestone for enabling the use of biolistics for gene therapy because it opened the technology up for those who previously could not engineer their own gun or who could not obtain one of the few spare guns from established groups. This product was also important because each ''home-built'' gene gun was different from every other one, so it was nearly impossible to standardize methods or compare efficiencies between different groups. One final advantage of the Helios gun relative to most home-built guns is that it is a 12-shot ''revolver'' gene gun allowing 12 transfections before the gun needs to be reloaded. In contrast, nearly all other gene guns were single-shot guns requiring reloading after each shot. Because each ''reload'' on older gene guns generally took about 1 minute to perform, the ability to more quickly reload the 12-shooter Helios and perform 12 transfections in a row greatly facilitated transfections of large numbers of cells or animals.
Sanford's pivotal incite that produced the gene gun revolutionized genetic engineering of a number of plant species, including soybeans and corn [reviewed in (9)]. Subsequent work demonstrated that biolistic gene guns could deliver genes not only into plant cells, but also into bacteria, yeast, and fungi [reviewed in (9)]. Biolistics was also the first technology able to genetically modify subcellular organelles, including chloroplasts (10) and mitochondria (11).
This work in other organisms laid the foundation for the application of gene guns for mammalian cells and intact animals. The first published demonstration of mammalian cell modification by biolistics was by Zelenin et al. demonstrating gene delivery into cultured mouse 3T3 cells in 1989 (12). This was followed by in vitro and in vivo gene gun-mediated gene delivery by groups from Agracetus published in 1990 (13) and by the Sanford-Johnston-Williams collaboration in 1991 (14). In the 1980s, these efforts to deliver plasmid DNA into living animals by gene gun occurred parallel to efforts by Jon Wolff's group to deliver plasmids as naked DNA into skeletal muscle by injection, which were published in 1990 (15). Prior to these observations, in vivo gene delivery could routinely be performed only by use of complex nonviral or viral vectors
for gene delivery. The ability to deliver simple plasmids into living cells in living animals by gene gun and by naked DNA injection were pivotal technological advances that enabled a variety of gene therapy applications. They particularly allowed one to transfect living animals or humans with vectors that were unencumbered vector chemicals or antigens.
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