From Molecular Biology to "Genetic Antibiotics"

FROM MOLECULAR BIOLOGY TO "GENETIC ANTIBIOTICS" MARK A. GOLDSMITH* The advent of sophisticated methodologies in molecular biology has prompted a substantial restructuring of basic research practice. The large, often impenetrable questions that formerly drove the study of normal biology and of pathology largely have been supplanted by more focused and refined investigation into the detailed molecular bases of highly specific processes. For example, broad theories of how genetics might contribute to malignancy have given way to concrete, direct tests of the actions ofoncogenes in transgenic mouse models [I]. Basic science now has at its disposal an ever-growing battery of powerful tools to clone, sequence, mutate, truncate, rearrange, express, delete, transfer, and assay the expression of genes Ofinterest. Imaginative applications of these methods at the bench routinely are permitting dramatic insights into the biology of humans and into the underlying events when things go awry. There is a growing impetus to transfer advanced biologic technology into the clinical arena to address the long list of critical problems that have remained refractory to traditional methods. Thus far this set of tools, which was developed for basic research, has reached clinical medicine largely in two areas. First, highly sensitive and specific diagnostic tools have devolved from the machinations of the molecular geneticist ; DNA probes—used to characterize foreign DNA (e.g., viruses), genetic polymorphisms, and mutations—are no longer the exclusive domain of the basic science laboratories. Second, the ability to obtain large quantities of pure (even "improved") human proteins for replacement The author expresses appreciation to Drs. William Rutter, Dino Dina, and Robert Ralston for interesting discussions about the principle of "genetic antibiotics," particularly for the suggestion of two-part drug systems; to Drs. Lloyd H. Smith, Arthur Weiss, Gary Koretzky, Ralph S. Goldsmith, and Denise Koo for helpful comments and editing. *Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115.© 1990 by The University of Chicago. AU rights reserved. 0031-5982/91/3401-0699$01.00 Perspectives in Biology and Medicine, 34, 1 ¦ Autumn 1990 \ 99 therapy—made possible by scaling up expression methods for DNA clones that have been a crucial component of the basic work-up of newly identified genes in the laboratory—has heralded the introduction of a revolutionary pharmacopoeia for the clinician. As the data base generated by basic research continues its exponential expansion, the opportunity and urgency to transfer the knowledge to the bedside likewise grow. Just as the design of scientific investigation now is limited primarily by one's imagination rather than by the technology , so is the development of advanced therapeutic modalities. The first generation of clinical applications of molecular biology are rudimentary in view of the rapidly moving currents in basic science. Although significant ethical and societal issues must be resolved before advanced genetic technology may be actually applied directly to patient care, physician -scientists who practice their arts at both the bench and the bedside now have enormous opportunities to combine medical awareness, technical might, and imagination to generate compelling new avenues for patient care. As an illustration of such an opportunity, I shall in the remainder of this discussion focus on one example of a commonplace methodology from the laboratory that, at least in theory, could be applied directly to some of the most challenging contemporary medical dilemmas. This case example will be explored from four perspectives: (a) the basic technology as used in the laboratory; (b) widely discussed applications to genetic diseases; (c) a higher form proposed recently by Dr. David Baltimore ; and (d) a proposed new family of "genetic antibiotics" that incorporates extant and new possibilities. A Basic Technology One basic experimental design that has become routine laboratory practice is the transfer of cloned genes from one cell to another. In its simplest form, genes on plasmids (small, circular bits of nonchromosomal DNA) are introduced readily into permeabilized bacteria (i.e., "transformation") where they are reproduced with great efficiency while remaining physically distinct from the bacterial genome. This amplified episomal DNA can then be recovered in large quantities for further manipulation. During the last decade, it has become relatively easy to extend the principles of transformation to eukaryotic cells. Thus, one can now...