History of Virology

Abstract

The history of virology can be traced as the personalities involved have described their concepts and published their experimental results. Although infections we now know as, e.g., rabies, yellow fever, smallpox, etc. were clinically evident in early human history, the initial isolation of individual viruses and their assignment to specific diseases did not occur until about 1898, 120 years ago, a proverbial drop in the bucket of time. Just one lifetime ago, Peter Medawar, awarded the Nobel Prize in Medicine and Physiology in 1960, defined viruses as a piece of nucleic acid surrounded by bad news.

The history of virology can be traced as the personalities involved have described their concepts and published their experimental results. Although infections we now know as, e.g., rabies, yellow fever, smallpox, etc. were clinically evident in early human history, the initial isolation of individual viruses and their assignment to specific diseases did not occur until about 1898, 120 years ago, a proverbial drop in the bucket of time. Just one lifetime ago, Peter Medawar, awarded the Nobel Prize in Medicine and Physiology in 1960, defined viruses as a piece of nucleic acid surrounded by bad news.

The early pioneers in virology had a very limited armamentarium on hand to classify or identify viruses as microbial agents. At the time of their initial discoveries, microscopes of sufficient power to see viral agents were not yet invented; cell cultures to grow viruses were unknown, and probes like antibodies or nucleic acids to mark an infectious agent were not available. Further, biophysical apparatuses like centrifuges or acrylamide gels to concentrate or separate viral proteins or nucleic acids did not exist. Eventually, the will for discovery caused such techniques to emerge. Their use not only defined modern virology and its classifications, but as virology developed it also provided insights that created contemporary cell and molecular biology, protein and structure/function study, immunology, epidemiology for infectious disease analysis, and emergence of treatment. A triumph of modern pharmacology is the formulation of vaccines and, recently, antiviral drugs. Vaccines changed the landscape of virology. Devastating infectious diseases like smallpox, which once killed or maimed millions of humans, have been eliminated, whereas others like poliomyelitis, measles, rubella (German measles), yellow fever, mumps, etc. can be well controlled and others, like influenza, managed. Antiviral therapeutics against HIV now markedly lessen the almost universal mortality rate formerly associated with AIDS. Further, viruses cause at least 20% of all cancers, and vaccines now routinely control liver cancers caused by hepatitis B virus as well as uterine, cervical, and penile cancers caused by several papilloma virus strains. Vaccines have provided the greatest punch-per-buck of any therapeutic regimen in medicine.

Now it is possible, in hindsight, to judge how correct or flawed were the initial concepts formed by early and even recent virologists about the diseases and causes they studied. For this article on the history of virology, selected principles and concepts are reviewed, together with the influences on and reasons for their evolution. Detailed descriptions of viruses that did or do cause plagues and their histories can be gleaned from the publications of McNeill (1976), Oldstone (2010), and Waterson and Wilkinson (1978).

The identification of viruses as infectious agents followed on the heels of pioneer work in the mid-1800s by Louis Pasteur and associates. During that period, the laboratory culturing process was developed for bacteria, which could be grown on enriched agar preparations or broths and were identifiable when the bacteria were fixed on glass slides, stained, and examined under the microscope. Bacteria were isolated by their retention on filters with specific pore sizes (Figure 1(a)). After their collection on filters, growth on agar and identification, specific bacteria could be linked with individual diseases by using Koch's (Henle–Koch) postulates (Figure 1 (a)). It was with this framework that the first viruses were uncovered (Figure 1(b)). In 1898, Dmitri Losifovich Ivanovski (Ivanovski, 1899), in Russia, and Martinus Beijerinck (Beijerinck, 1899), in the Netherlands, demonstrated that the material responsible for a disease of tobacco plants, instead of being retained, passed through the then smallest pore-sized filter used in the Pasteur–Chamberland apparatus without losing infectivity. Thus, the material at the bottom of the filter-containing flask was smaller than bacteria and proved to remain infective when transferred to an uninfected recipient (plant) of the type from which it was first retrieved (Figure 1(b)). Ivanovsky and Beijerinck identified the first virus, a plant virus they named the tobacco mosaic virus. Almost concurrently, Friedrich Loeffler and Paul Frosch (Loeffler and Frosch, 1898), in Germany, utilizing a similar approach, concluded that the agent causing foot-and-mouth disease of cattle also passed through porcelain filters and induced symptoms of disease when inoculated back into healthy cattle (Figure 1(b)). These observations, highly controversial at the time, provided the basis for defining viruses as subcellular entities that caused distinct forms of tissue destruction, which became hallmarks of specific diseases. The uniqueness of this detective work is even more dramatic when one considers that the infectious virus particles were too small to see and could not grow on the culture media available (Table 1 ). Visualization of viruses awaited the use of electron microscopy in the mid-1930s, and the culturing of living cells necessary for viral replication was not possible until the late 1940s to early 1950s. Figure 1(a) illustrates the beginning of microbiology, and Figure 1(b) illustrates the first viral isolations and lists the conceptual problems such virologists had while proving Koch's postulates. Conceptually, a viral replicating agent was distinguishable from a toxin when dilution of the supernatant material that passed through the Pasteur– Chamberland filter lost potency on injection into the appropriate host (then it was a toxin). In contrast, if the diluted material retained potency after injection, it was a replicating agent. Yet, not all material obtained from an infected source and passed through a Pasteur–Chamberland-like filter followed by transmission of infectious supernatant material proved to be a virus (Figure 1(c)). In this illustration, filter passage-infected material from scrapie-infected sheep caused a similar disease when inoculated back into healthy sheep, the natural host. However, not until the 1980–1990 did research show that this infectious material did not contain nucleic acids but rather that disease was transmitted by the misfolded abnormal prion protein (termed PrPres or PrPsc) from infected sheep (Table 1).

Figure 1.

Table 1.

Selected milestones for and in virology

Date(s)	Virologists/investigators	Discovery
400 BCE	Hippocrates	Greek physician, father of medicine, epidemiologic observations of many viral diseases
1796	E. Jenner	Application of cowpox virus for vaccination against smallpox, inflammation origins of virology and immunology
1846	P. Panum	Immunologic memory (protection) against reinfection (measles). Conceptual basis for vaccine strategy
1857	L. Pasteur, R. Koch	Founding of microbiology
1858	C. Darwin, A. Wallace	Concepts of evolutionary progression, natural selection
1865	G. Mendel	Founding of genetics
1883	E. Metchnikoff, P. Ehrlich	Founding of immunology
1885	L. Pasteur, E. Roux	Development of rabies vaccine
1892–98	D. Ivanovsky, M. Beijerinck	First demonstrations of a filterable plant virus: tobacco mosaic virus
1898	F. Loeffler, P. Frosch	First demonstration of a filterable animal virus: foot-and-mouth disease virus
1900	J. Carroll, J. Lazear, A. Agramonte, W. Reed, C. Finlay, W. Gorgas	First human virus: yellow fever virus, first use of consent form for human clinical investigation, identify mosquito as a transmitting agent, control of virus by elimination of mosquito breeding sites
1904–08	V. Ellermann, O. Bang, H. Vallee, H. Carre	First demonstration of a leukemia-causing virus, retrovirus
1908	C. von Pirquet	First report of virus causing immunosuppression: measles virus
1909	K. Landsteiner, E. Popper	Isolation of poliomyelitis virus
1911	J. Goldberger	Discovery of measles virus
1911	P. Rous	First demonstration of a solid tumor virus: Rous sarcoma virus
1915	F. Twort	Discovery of bacteriophages
1917	F. d’Herelle	Bacteriophages, plaque assay
1919	A. Löwenstein	Discovery of herpes simplex virus
1923–28	A. Carrel, H. Maitland, M. Maitland	Tissue culture of embryo explants and first tissue culture cultivation of virus: Rous virus, vaccinia virus
1928	R. Lancefield, E. Lennette, others	Beginning of viral disease diagnosis
1931	J. Furth	Use of mice as a host for viruses
1931	A. Woodruff, E. Goodpasture	Use of embryonated hen's eggs as a host for viruses
1933	W. Smith, C. Andrewes, P. Laidlaw	Isolation of human influenza virus
1933	R. Shope	Rabbit papillomavirus: first DNA tumor virus
1933	A. Tiselius	Development of electrophoresis
1936	J. Cuillé, P.-L. Chelle	Transmission of scrapie to normal sheep by cell-free material from diseased sheep
1936	P. Rous, J. Beard	Rabbit papillomavirus induces carcinomas in a different species
1936	C. Armstrong, T. Rivers, E. Traub	Discovery of lymphocytic choriomeningitis virus: the first arenavirus
1937–51	M. Theiler and others	Development of 17D strain human yellow fever vaccine: made in animal and embryonic cultures
1939	G. Kausche, P. Ankuch, H. Ruska	First electron micrograph of a virus: tobacco mosaic virus
1939	M. Debbruck, E. Ellis	Identification of the one-step virus growth curve
1941	G. Hirst	Discovery of influenza virus hemagglutination, hemagglutination inhibition test
1941	M. Gregg	Discovery of rubella virus congenital abnormalities
1944	O. Avery, C. MacLeod, M. McCarty	Identification of DNA as the material of inheritance
1945	T. Francis, J. Salk, G. Hirst, F. Davenport, E. Kilbourne, others	Development of inactivated influenza vaccines
1946	W. Stanley, J. Summer, J. Northrop	Preparation of a viral protein in a pure form: tobacco mosaic virus
1948–55	J. Enders, T. Weller, F. Robbins, H. Eagle	Routine use of tissue culture to grow and study viruses, development of optimal media for growing cells
1953	J. Watson, F. Crick, M. Wilkins, R. Franklin	Discovery of the structure of DNA
1953	A. Coons	Development of immunofluorescence
1954	J. Salk, J. Youngner, T. Francis, others	Development of inactive poliomyelitis vaccine
1954	B. Sigurdsson	Development of the concept of slow viruses (maedi-visna virus)
1954	W. Rowe	Role of thymus in immune responses to virus
1954–61	J. Salk, A. Sabin, H. Koprowski, J. Enders, S. Katz, S. Krugman	Development of poliomyelitis virus vaccine, development of measles virus vaccine: made in tissue culture
1956	H. Fraenkel-Conrat, B. Singer	Discovery of the infectivity of viral RNA (tobacco mosaic virus)
1956	M. Smith, W. Rowe, T. Weller	Discovery of cytomegalovirus
1957	A. Isaacs, J. Lindenmann	Discovery of interferon
1957	J. Enders, M. Hilleman, A. Gershon, S. Katz, S. Plotkin, M. Takahashi, others	Development of vaccines against measles, mumps, rubella, hepatitis A, hepatitis B
1959	A. Sabin, H. Cox, H. Koprowski	Development of attenuated live-virus poliomyelitis vaccine
1959	S. Brenner, R. Horne	Invention of negative stain electron microscopy
1959	R. Porter, G. Edelman, A. Nisonoff	Discovery of the structure and molecular function of antibodies
1959	R. Yalow, S. Berson, F. Dixon	Development and use of radioimmune assays
1950s–70s	S. Luria, M. Delbruck, J. Monod, A. Lwoff, F. Jacob, S. Brenner, M. Nirenberg, S. Ochoa, H. Khorana, E. Wollman, A. Hershey, S. Benzer, S. Cohen, D. Nathans, R. Dulbecco, D. Baltimore, H. Smith, W. Arber, J. Kates, H. Temin, P. Sharp, others	Quantitative plaque assay, origins of molecular biology, and molecular virology
1950s–80s	B. Sigurdsson, B. Blumberg, C. Gajdusek, S. Prusiner, others	Persistent, latent, and slow virus infections, prions
1960s–70s	G. Palade, A. Claude, K. Porter, C. DeDuve	Description and techniques for fine structure and biochemistry of cellular organelles
1962	A. Klug, D. Caspar	Discovery of the principles of icosahedral virus structure
1967	J. Maizel, U. Laemmi	Discovery of SDS polyacrylamide gel electrophoresis
1969–76	R. Huebner, P. Vogt, M. Bishop, H. Varmus, R. Weinberg, others	Oncogenes
1970s–2000s	R. Zinkernagel, P. Doherty, M. Oldstone, B. Fields, B. Moss, A. Notkins, R. Ahmed, F. Chisari, N. Nathanson, others	Major histocompatibility restriction and cytotoxic T lymphocytes, immune-mediated viral diseases, molecular pathogenesis
1973	D. Nathans	Completion of the restriction map of a viral genome (SV40)
1974	G. Köhler, C. Milstein	Development of monoclonal antibodies
1975	B. Blumberg, B. Larouze, W. London, others	Discovery of the relationship of hepatitis B virus with hepatocellular carcinoma
1976	T. Diener	Discovery of viroids (infectious naked RNA molecules)
1976	K. Johnson, P. Webb, J. Lange, F. Murphy, J. McCormick, others	Discovery of Ebola virus
1977	World Health Organization, D.A. Henderson, F. Fenner, and many health workers and virologists	Eradication of smallpox as a disease that killed over 300 million people in the twentieth century
1978–83	S. Harrison, A. Olson, J. Hogle, M. Rossman, R. Rueckert	First atomic structure of a plant (tomato bushy stunt) and animal (poliovirus, rhinovirus) virus
1979	D. Lane, L. Crawford, D. Linzer, A. Levine	SV40T-antigen-p53, virus host cell interaction-tumor suppressors
1980s–90s	J. Strauss, E. Strauss, and others	Molecular analysis, structure/function of yellow fever
1980s–2000s	B. Roizman, J. Subak-Sharpe, E. Kieff, P. Spears, E. Wagner, J. Nelson, E. Goodpasture, J. Stevens, A. Notkins	Genetic map and function of genes of herpes viruses, herpes latency
1980s–2000s	H. zur Hausen, D. Galloway, D. Lowy, I. Frazer, others	Recognition of subtypes of papillomaviruses associated with cervical and penile cancer and development of papillomavirus vaccine
1981	J. Skehel, D. Wiley, I. Wilson, others	Structure/function of influenza virus hemagglutinin, first atomic structure of a glycoprotein
1981–84	R. Gallo, F. Barre-Sinoussi, L. Montagnier, Y. Hinuma, J. Chermann, others	First human retrovirus
1984–2000	M. Hillemann, others	First molecular recombinant virus vaccine: hepatitis B virus, first vaccine to successfully treat cancer: hepatitis B virus-induced liver cancer
1985	K. Mullis, others	Invention of polymerase chain reaction (PCR)
1987	S. Broder, H. Mitsuya, M. Fischl, D. Richman, others	Development of first anti-HIV drug approved by the FDA
1987	M. Capecchi, M. Evans, O. Smithies	Development of knockout and other genetically manipulated mice
1988–2000s	M. Eigen, C. Weissmann, J. Holland, E. Domingo, J.C. de la Torre, R. Adino, E. Koonin, A. Gibbs, others	Development of modern concepts in viral evolution and quasispecies
1991	C. Venter, H. Smith	Invention of shotgun cloning methods
1993	S. Falkow	Molecular criteria for proof of viral disease causation: revisiting the Henle–Koch postulates
1994–2000s	K.-K. Conzelmann, M. Schnell, T. Mebatsion, P. Palese, J.C. de la Torre, Y. Kawaoka	Development of reverse genetics for negative-strand RNA virus
1990–present	R. Ahmed, M. Bevin, M. Slifka, and others	Kinetics, cell, and molecular basis of T cell and B cell generation and immunologic memory
1998–2006	R. Ahmed, A. Zajac, E.J. Wherry, M. Oldstone, D. Brooks, others	Persistent virus infections associated with T cell exhaustion and caused by negative immune response regulators PD-1 and IL-10
1990–present	W.I. Lipkin, J. diRossi, D. Ganem, H. Virgin, and others	Modern molecular detection of new viruses
2003	C. Urbani, J. Peiris, S. Lai, A. Osterhaus, others	Discovery of SARS coronavirus, the first viral pandemic of the twentyfirst century
2005	J. Taubenberger, P. Palese, T. Tumpey, A. Garcia-Sastre, Y. Kawaoka, others	Molecular reconstruction, sequencing of the 1918–19 influenza virus; determining viral genes associated with pathogenesis
2005	T. Wakita, C. Rice, F. Chisari	Manipulation of virus and cells for first in vitro hepatitis C virus culture system
2000s	B. Beutler, J. Hoffmann, S. Akari, C. Janeway, R. Medzhitov	Discovery of cell-surface molecules activated by innate immunity and pathways involved
2000s	R. Steinman, Z. Cohn, others	Discovery of the dendritic cell and its role in adaptive immunity
2000–2015	World Health Organization – many health workers and virologists	Planned eradication/elimination of poliomyelitis virus and measles virus (by 2015) as a disease

Many viral infections cause acute illnesses. That is, the causative virus enters the body, multiplies in one or more tissues, and spreads locally through the blood, along nerves, or along the respiratory or gut tracts. The incubation period of 2 days to 2 or 3 weeks is followed by signs and symptoms of disease and local or widespread tissue damage. Viruses can be isolated from the patient's blood (serum or blood cells), secretions or washes for a short time just before and after the appearance of symptoms or from their infected tissues. Afterward, the infected host either recovers from the infection, and is often blessed with lifelong immunity to that virus, or dies during the acute phase of illness. Although the majority of life-threatening and debilitating acute virus infections are now controlled through vaccination, it is worthwhile considering the consequences of acute infections like smallpox, measles, and yellow fever in the prevaccine era. Smallpox, before its eradication in 1980, killed over 300 000 000 persons just in the twentieth century and caused a mortality rate of approximately 33% (reviewed in McNeill, 1976, and Oldstone, 2010). In the sixteenth century, when Native Americans were inadvertently exposed to infectious viruses, often carried by Europeans colonizing the New World, the result was a reduction of the native population in Mexico and Latin America from an estimated 20 million to 2 million. This devastating depopulation came primarily from smallpox and measles infections, since these viruses had never before existed in the New World (Oldstone, 2010). Smallpox has now been eliminated from our planet and measles virus controlled, at least in most developed countries. However, measles virus infection was and remains a serious disease today with approximately one per thousand infected persons developing severe destruction of the central nervous system requiring institutionalization. Yellow fever spread up the Mississippi River, carried by infected passengers incubating the disease as they traveled on riverboat(s), embarking from the Caribbean to New Orleans on 24 July 1878, moving on to Vicksburg a few days later and arriving in Memphis, where the first case occurred by 14 August (reviewed in Oldstone, 2010). At that time, no one knew that the infection was transmitted by the bite of Anopheles Aedes aegypti mosquitoes. The mosquito sucks blood from an infected person, then transmits the virus by biting an uninfected susceptible person. At the time of the yellow fever outbreak in Memphis, the city population was approximately 98 000 persons. By the end of the two-month epidemic, 20 000 people had fled Memphis. Of those who stayed, 77% were infected and 70% died. The economic result was the destruction of Memphis as a commercial capital in the American South, to be replaced by Atlanta. As reported in the New York Herald newspaper by writer Robert Blakeslee, on assignment from New York City to Memphis to cover the yellow fever epidemic, “The city was almost deserted … We had not gone far, however, before the evidence of the terrible condition of things became apparent. The first thing in the shape of a vehicle that I saw was a truck (wagon), loaded with coffins, going around to collect the dead. As this was within four blocks of the depot you may imagine how soon I came to a realizing sense of the desolation. Two blocks further on, coffins were piled on tiers on the sidewalk in front of the undertaker's shop, and we were compelled to walk between them … Everyone was thoroughly frightened, a young doctor said to me. ’It takes a man of great moral courage to stay in this place. You talk with a man tonight and tomorrow hear that he is in the grave’” (reviewed in Oldstone, 2010). To those who consider this part as ancient and perhaps nonrelevant contemporary history, it is well to recall that during the 1918–19 influenza epidemic in the USA, over 600 000 people died in less than 2 years. In the city of Philadelphia and some other locales, the supply of coffins ran out causing the dead to be buried in mass graves. As recently as the 1980s–90s, a similar scenario played out in parts of Africa when the AIDS epidemic caused by HIV resulted in widely publicized mass deaths and still do in parts of Africa and Asia.

Now these and many other acute virus infections are controlled by vaccination or antivirals and public health policies when and where they are instituted.

Distinct from those acute infections are persistent infections, a major health problem today. In persistent infection, the immune response fails to completely remove viruses from the body, and those viruses remaining then persist in their host for months or years. For infections like those by hepatitis B and C viruses and HIV, viruses can be recovered from the patients’ blood for years, during the long course of infection. Although all components (antibodies and T cells) of the immune response are generated during those infections, the T cell response is compromised (by exhaustion or hyporesponsiveness) and is not capable of eliminating the infectious agent.

Table 1 lists events that have impacted the science of virology and its influence on not only diseases but also on the larger milieu of basic research. A more extensive list of important events, observations, and highlights in the discipline of virology has been compiled by Fred Murphy, a long-time contributor to the field, and is accessible at http://www.utmb.edu/virusimages/