Virologists - History of Virology

History of Virology

The word virus appeared in 1599 and originally meant "venom".

A very early form of vaccination known as variolation was developed several thousand years ago in China. It involved the application of materials from smallpox sufferers in order to immunize others. In 1717 Lady Mary Wortley Montagu observed the practice in Istanbul and attempted to popularize it in Britain, but encountered considerable resistance. In 1796 Edward Jenner developed a much safer method, using cowpox to successfully immunize a young boy against smallpox, and this practice was widely adopted. Vaccinations against other viral diseases followed, including the successful rabies vaccination by Louis Pasteur in 1886. The nature of viruses however was not clear to these researchers.

In 1892 Dimitri Ivanovski showed that a disease of tobacco plants, tobacco mosaic disease, could be transmitted by extracts that were passed through filters fine enough to exclude even the smallest known bacteria. In 1898 Martinus Beijerinck repeated Iwanowski's work but went further and passed the "filterable agent" from plant to plant, found the action undiminished, and concluded it infectious—replicating in the host—and thus not a mere toxin. He called it contagium vivum fluidum. The question of whether the agent was a "living fluid" or a particle was however still open.

In 1903 it was suggested for the first time that transduction by viruses might cause cancer. In 1908 Bang and Ellerman showed that a filterable virus could transmit chicken leukemia, data largely ignored till the 1930s when leukemia became regarded as cancerous. In 1911 Peyton Rous reported the transmission of chicken sarcoma, a solid tumor, with a virus, and thus Rous became "father of tumor virology". The virus was later called Rous sarcoma virus 1 and understood to be a retrovirus. Several other cancer-causing retroviruses have since been described.

The existence of viruses that infect bacteria (bacteriophages) was first recognized by Frederick Twort in 1911, and, independently, by Felix d'Herelle in 1917. As bacteria could be grown easily in culture, this led to an explosion of virology research.

The cause of the devastating Spanish flu pandemic of 1918 was initially unclear. In late 1918, French scientists showed that a "filter-passing virus" could transmit the disease to people and animals, fulfilling Koch's postulates.

In 1926 it was shown that scarlet fever is caused by a bacterium that is infected by a certain bacteriophage.

While plant viruses and bacteriophages can be grown comparatively easily, animal viruses normally require a living host animal, which complicates their study immensely. In 1931 it was shown that influenza virus could be grown in fertilized chicken eggs, a method that is still used today to produce vaccines. In 1937, Max Theiler managed to grow the yellow fever virus in chicken eggs and produced a vaccine from an attenuated virus strain; this vaccine saved millions of lives and is still being used today.

Max Delbrück, an important investigator in the area of bacteriophages, described the basic "life cycle" of a virus in 1937: rather than "growing", a virus particle is assembled from its constituent pieces in one step; eventually it leaves the host cell to infect other cells. The Hershey-Chase experiment in 1952 showed that only DNA and not protein enters a bacterial cell upon infection with bacteriophage T2. Transduction of bacteria by bacteriophages was first described in the same year.

In 1949 John F. Enders, Thomas Weller and Frederick Robbins reported growth of poliovirus in cultured human embryonal cells, the first significant example of an animal virus grown outside of animals or chicken eggs. This work aided Jonas Salk in deriving a polio vaccine from deactivated polio viruses; this vaccine was shown to be effective in 1955.

The first virus that could be crystalized and whose structure could therefore be elucidated in detail was tobacco mosaic virus (TMV), the virus that had been studied earlier by Ivanovski and Beijerink. In 1935, Wendell Stanley achieved its crystallization for electron microscopy and showed that it remains active even after crystallization. Clear X-ray diffraction pictures of the crystallized virus were obtained by Bernal and Fankuchen in 1941. Based on such pictures, Rosalind Franklin proposed the full structure of the tobacco mosaic virus in 1955. Also in 1955, Heinz Fraenkel-Conrat and Robley Williams showed that purified TMV RNA and its capsid (coat) protein can self-assemble into functional virions, suggesting that this assembly mechanism is also used within the host cell, as Delbrück had proposed earlier.

In 1963, the Hepatitis B virus was discovered by Baruch Blumberg who went on to develop a hepatitis B vaccine.

In 1965, Howard Temin described the first retrovirus: a virus whose RNA genome was reverse transcribed into complementary DNA (cDNA), then integrated into the host's genome and expressed from that template. The viral enzyme reverse transcriptase, which along with integrase is a distinguishing trait of retroviruses, was first described in 1970, independently by Howard Temin and David Baltimore. The first retrovirus infecting humans was identified by Robert Gallo in 1974. Later it was found that reverse transcriptase is not specific to retroviruses; retrotransposons which code for reverse transcriptase are abundant in the genomes of all eukaryotes. About 10-40% of the human genome derives from such retrotransposons.

In 1975 the functioning of oncoviruses was clarified considerably. Until that time, it was thought that these viruses carried certain genes called oncogenes which, when inserted into the host's genome, would cause cancer. Michael Bishop and Harold Varmus showed that the oncogene of Rous sarcoma virus is in fact not specific to the virus but is contained in the genome of healthy animals of many species. The oncovirus can switch this pre-existing benign proto-oncogene on, turning it into a true oncogene that causes cancer.

1976 saw the first recorded outbreak of Ebola hemorrhagic fever, a highly lethal virally transmitted disease.

In 1977, Frederick Sanger achieved the first complete sequencing of the genome of any organism, the bacteriophage Phi X 174. In the same year, Richard Roberts and Phillip Sharp independently showed that the genes of adenovirus contain introns and therefore require gene splicing. It was later realized that almost all genes of eukaryotes have introns as well.

A worldwide vaccination campaign led by the UN World Health Organization resulted in the eradication of smallpox in 1979.

In 1982, Stanley Prusiner discovered prions and showed that they cause scrapie.

The first cases of AIDS were reported in 1981, and HIV, the retrovirus causing it, was identified in 1983 by Luc Montagnier, Françoise Barré-Sinoussi and Robert Gallo. Tests detecting HIV infection by detecting the presence of HIV antibody were developed. Subsequent tremendous research efforts turned HIV into the best studied virus. Human Herpes Virus 8, the cause of Kaposi's sarcoma which is often seen in AIDS patients, was identified in 1994. Several antiretroviral drugs were developed in the late 1990s, decreasing AIDS mortality dramatically in developed countries.

The Hepatitis C virus was identified using novel molecular cloning techniques in 1987, leading to screening tests that dramatically reduced the incidence of post-transfusion hepatitis.

The first attempts at gene therapy involving viral vectors began in the early 1980s, when retroviruses were developed that could insert a foreign gene into the host's genome. They contained the foreign gene but did not contain the viral genome and therefore could not reproduce. Tests in mice were followed by tests in humans, beginning in 1989. The first human studies attempted to correct the genetic disease severe combined immunodeficiency (SCID), but clinical success was limited. In the period from 1990 to 1995, gene therapy was tried on several other diseases and with different viral vectors, but it became clear that the initially high expectations were overstated. In 1999 a further setback occurred when 18-year-old Jesse Gelsinger died in a gene therapy trial. He suffered a severe immune response after having received an adenovirus vector. Success in the gene therapy of two cases of X-linked SCID was reported in 2000.

In 2002 it was reported that poliovirus had been synthetically assembled in the laboratory, representing the first synthetic organism. Assembling the 7741-base genome from scratch, starting with the virus's published RNA sequence, took about two years. In 2003 a faster method was shown to assemble the 5386-base genome of the bacteriophage Phi X 174 in 2 weeks.

The giant mimivirus, in some sense an intermediate between tiny prokaryotes and ordinary viruses, was described in 2003 and sequenced in 2004.

The strain of Influenza A virus subtype H1N1 that killed up to 50 million people during the Spanish flu pandemic in 1918 was reconstructed in 2005. Sequence information was pieced together from preserved tissue samples of flu victims; viable virus was then synthesized from this sequence. The 2009 flu pandemic involved another strain of Influenza A H1N1, commonly known as "swine flu".

By 1985, Harald zur Hausen had shown that two strains of Human papillomavirus (HPV) cause most cases of cervical cancer. Two vaccines protecting against these strains were released in 2006.

In 2006 and 2007 it was reported that introducing a small number of specific transcription factor genes into normal skin cells of mice or humans can turn these cells into pluripotent stem cells, known as Induced Pluripotent Stem Cells. The technique uses modified retroviruses to transform the cells; this is a potential problem for human therapy since these viruses integrate their genes at a random location in the host's genome, which can interrupt other genes and potentially causes cancer.

In 2008, Sputnik virophage was described, the first known virophage: it uses the machinery of a helper virus to reproduce and inhibits reproduction of that helper virus. Sputnik reproduces in amoeba infected by mamavirus, a relative of the mimivirus mentioned above and the largest known virus to date.

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