Is Virology Dead?

Mark Twain once remarked that the reports of his death were greatly exaggerated. So too, the death of virology. In certain quarters, it is now fashionable to declare the passing of virology. “Viruses are retro,” a faculty colleague once told me, deadly serious. We have heard this before. In 1967, the U.S. Surgeon General allegedly proclaimed, “The time has come to close the book on infectious disease. We have basically wiped out infection in the United States” (1). This was before the arrival of AIDS and severe acute respiratory syndrome (SARS) and the discovery of hepatitis C virus, before the fear of an avian flu pandemic and bioterrorism. Virology was once held in high esteem. In the first half of the 20th century, plant viruses held center stage. Studies of mosaic disease of tobacco revealed the existence of a new class of infectious agents smaller than bacteria, and tobacco mosaic virus taught us that viruses could be crystallized, disassembled, and reassembled into an infectious form: “life” could be studied with chemical approaches (2, 3). In the 1950s and 1960s, viruses that infect bacteria played a central role in the biological sciences. They formed the basis of the Hershey-Chase experiment, the first widely accepted evidence that DNA is the genetic material (4). Bacteriophage also led to the discovery of mRNA and the triplet nature of the genetic code and played a leading role in the birth of molecular biology (5). The 1970s and 1980s were a golden age for animal virology. The small genomes of many animal viruses and the ease of introducing them into cells made them the model organisms of choice to study eukaryotic cells. mRNA splicing, transcriptional enhancers, oncogenes, tumor suppressor proteins, antiapoptotic proteins, cellular trafficking signals and pathways, major histocompatibility complex (MHC) restriction, and much fundamental cell biology and biochemistry were discovered through studies of animal viruses (6). The roster of Nobel Prizes awarded for studies of viruses is long and unequaled. The success of virology enabled the ascendancy of other fields. Restriction mapping, gene transfer into animal cells, directed mutagenesis, and whole-genome sequencing were developed to analyze small viral genomes (7–14). These powerful methods ushered in the recombinant DNA era and were in turn applied to studying cellular genes as well. In fact, much of genetic engineering, at least in the early days, centered on converting the much larger cellular genomes into virus-sized bits of genetic information, which could then be analyzed by the methods used so successfully on the viruses themselves. With the adoption of molecular cloning techniques by cell biologists and geneticists, virologists no longer had a monopoly on insights into the innermost workings of cells. Now that we can clone and study cellular genes and have sophisticated methods to analyze cells and whole organisms, so the argument goes, why settle for studying viruses? To the cognoscenti, the real attraction of viruses was not only these methodological advantages but also the intimate relationship of viruses with their host cells. Because viruses depend on cellular machinery to replicate, they need to manipulate crucial regulatory nodes of cells to reprogram them into virus-producing factories (or into safe havens while waiting for the signal to replicate). By studying how viruses work the levers that control cell growth and behavior, and how cells fight back to maintain their sovereignty, important cellular processes are revealed. Thus, many aspects of signal transduction, cell cycle control, regulation of gene expression, immunology, and carcinogenesis were elucidated by studies of viruses and their interactions with host cells. Indeed, with their large population sizes, short generation times, and high rate of mutation, viruses are ideal evolutionary probes of cells. We may pride ourselves on the power of functional genomics screens, next-generation DNA sequencing, and sophisticated bioinformatics and proteomic analysis to dissect cellular activities, but these tools are no match for millions of years of fast-track viral evolution. As well as teaching us about how cells work, viruses provide us the means to manipulate cells. Virus particles are miniature, highly efficient gene delivery machines that are used in thousands of laboratories around the world to transfer genes into cells for research purposes. Viruses have also been used as vectors to treat human genetic disease and cancer and are being tested as novel vaccine platforms (15, 16). Although it is possible to incorporate genes into chemical nanoparticles and derivatize them with peptides and antibodies to direct them to specific tissues, these are primitive contraptions, crude Model T’s compared to the sleek Lamborghiniviridae. And virus-mediated gene transfer is not restricted to the laboratory or the clinic. Viruses can also transfer genes between cells in nature, opening up new evolutionary opportunities. In fact, a large fraction of our own genome originated from the remnants of ancient viruses (17). These confrontations between viruses and cells helped mold cellular genomes over evolutionary time and have been captured in flagrante today in wild koalas, where an infectious retrovirus is becoming established in the germ line, adopting an endogenous existence (18). We can also learn from viruses how to alter cell function. Viral proteins can be used to modulate cell behavior, and the design of novel proteins modeled on viral proteins is a new frontier in synthetic biology. A small papillomavirus protein has been used as an all-purpose transmembrane scaffold to reprogram cells to undergo red blood cell differentiation or to resist HIV infection, and plans are afoot to utilize a small adenovirus protein to manipulate a wide range of nuclear functions (19–21). Finally, the small size of viral genomes permits us to construct “designer viruses” in the laboratory (22). We can resurrect long-dead pathogenic viruses