User:Graham Beards/viruses/History of virology

From Wikipedia, the free encyclopedia

The history of virology – the scientific study of viruses and the infections they cause – begins in the closing years of the 19th century. Although Louis Pasteur and Edward Jenner developed the first vaccines to protect against viral infections, they did not know that viruses existed.

The first evidence of the existence of viruses came from experiments with filters that had pores small enough to retain bacteria. In 1892, Dmitry Ivanovsky used one of these filters to show that sap from a diseased tobacco plant remained infectious to healthy tobacco plants despite having been filtered. Martinus Beijerinck called the filtered, infectious substance a "virus" and this discovery is considered to be the beginning of virology. In the 20th century many viruses were discovered.

Early virologists[edit]

Martinus Beijerinck in his laboratory in 1921

Despite his other successes, Louis Pasteur (1822–1895) was unable to find a causative agent for rabies and speculated about a pathogen too small to be detected using a microscope.[1] In 1884, the French microbiologist Charles Chamberland (1851–1931) invented a filter – known today as the Chamberland filter – that had pores smaller than bacteria. Thus, he could pass a solution containing bacteria through the filter and completely remove them from the solution.[2] In 1892, the Russian biologist Dmitry Ivanovsky (1864–1920) used this filter to study what is now known as the tobacco mosaic virus. His experiments showed that crushed leaf extracts from infected tobacco plants remain infectious after filtration. Ivanovsky suggested the infection might be caused by a toxin produced by bacteria, but did not pursue the idea.[3]

In 1898, the Dutch microbiologist Martinus Beijerinck (1851–1931) repeated the experiments and became convinced that the filtered solution contained a new form of infectious agent.[4] He observed that the agent multiplied only in cells that were dividing and he called it a contagium vivum fluidum (soluble living germ) and re-introduced the word virus.[3] Beijerinck maintained that viruses were liquid in nature, a theory later discredited by the American biochemist and virologist Wendell Meredith Stanley (1904–1971), who proved they were particles.[3] In the same year Friedrich Loeffler (1852–1915) and Paul Frosch (1860–1928) passed the first animal virus through a similar filter and discovered the cause of foot-and-mouth disease.[5]

In 1881, Carlos Finlay (1833–1915), a Cuban physician, first suggested that mosquitoes were carrying the cause of yellow fever,[6] a theory that was proved in 1900 by Walter Reed (1851–1902). During 1901 and 1902, William Crawford Gorgas (1854–1920) organised the destruction of the mosquitoes' breeding habitats in Cuba, which dramatically reduced the prevalence of the disease.[7] Gorgas later organised the elimination of the mosquitoes from Panama, which allowed the Panama Canal to be opened in 1914.[8] The virus was finally isolated by Max Theiler (1899–1972) in 1932 who went on to develop a successful vaccine.[9]

By 1928 enough was known about viruses to enable Thomas Milton Rivers (1888–1962) to write the first book about all known viruses and his Filtrable Viruses was published in 1928. Rivers, who survived typhoid fever at the age of twelve, went on to have a distinguished career in virology. He was born in Jonebro, Georgia USA, was awarded a BA degree from Emory College in 1909 and graduated in medicine at Johns Hopkins University in 1915. In 1926, he was invited to speak at a meeting organised by the Society of American Bacteriology where he said for the first time, "Viruses appear to be obligate parasites in the sense that their reproduction is dependent on living cells."[10]

That viruses were particles was not considered unnatural and fitted in nicely with the germ theory. It is assumed that Dr. J. Buist of Edinburgh was the first person to see virus particles in 1886, when he reported seeing "micrococci" in vaccine lymph. But he had probably seen clumps of vaccinia virus.[11] In the years that followed, as optical microscopes were improved "inclusion bodies" were seen in many virus-infected cells, but these aggregates of virus particles were still too small to reveal any detailed structure. It was not until the invention of the electron microscope in 1931 by the German engineers Ernst Ruska (1906–1988) and Max Knoll (1887–1969),[12] that virus particles, especially bacteriophages, were shown to have a complex structure. The sizes of viruses determined using this new microscope fitted in well with those estimated by filtration experiments. Viruses were expected to be small, but the range of sizes came as a surprise. Some were only a little smaller than the smallest known bacteria, and the smaller viruses were of similar sizes to complex organic molecules.[13]

In 1935, Wendell Stanley examined the tobacco mosaic virus and found it was mostly made of protein.[14] In 1939, Stanley and Max Lauffer (1914) separated the virus into protein and RNA parts.[15] The discovery of RNA in the particles was important because in 1928, Fred Griffith (c.1879–1941) provided the first evidence that its "cousin", DNA, formed genes.[16]

In Pasteur's day, and for many years after his death the word "virus" was used to describe any cause of infectious disease. Painstaking work, by many bacteriologists, soon discovered the cause of numerous infections. However, some infections remained, many of them horrendous, but for which no bacterial cause could be found. These agents were invisible and could only be grown in living animals. The discovery of viruses was the key that unlocked the door that withheld the secrets of the cause of these mysterious infections. And, although Koch's postulates could not be fulfilled for many of these infections, this did not stop the pioneer virologists from looking for viruses in infections for which no other cause could be found.[17]

Bacteriophages[edit]

Bacteriophage

Bacteriophages are viruses that infect bacteria. There are over 5,100 types of bacteriophages. They are important in marine ecology: as the infected bacteria burst, carbon compounds are released back into the environment, which stimulates fresh organic growth. Bacteriophages are useful in scientific research because they are harmless to humans and can be studied easily. These viruses can be a problem in industries that produce food and drugs by fermentation and depend on healthy bacteria. Some bacterial infections are becoming difficult to control with antibiotics, so there is a growing interest in the use of bacteriophages to treat infections in humans.[18]

The structure of a typical bacteriophage

Discovery[edit]

Bacteriophages were discovered in the early 20th century, by the English bacteriologist Frederick Twort (1877–1950).[19] But before this time, in 1896, the bacteriologist Ernest Hanbury Hankin (1865–1939) reported that something in the waters of the River Ganges could kill Vibrio cholera – the cause of cholera. Whatever it was in the water could be passed through filters that remove bacteria but was destroyed by boiling.[20] Twort discovered the action of bacteriophages on staphylococci bacteria. He noticed that when grown on nutrient agar some colonies of the bacteria became watery or "glassy". He collected some of these watery colonies and passed them through a Chamberland filter to remove the bacteria and discovered that when the filtrate was added to fresh cultures of bacteria, they in turn became watery.[19] He proposed that the agent might be "an amoeba, an ultramicroscopic virus, a living protoplasm, or an enzyme with the power of growth".[20]

Félix d'Herelle (1873–1949) was a mainly self-taught French-Canadian microbiologist. In 1917 he discovered that "an invisible antagonist", when added to bacteria on agar, would produce areas of dead bacteria.[19] The antagonist, now known to be a bacteriophage could pass through a Chamberland filter. He accurately diluted a suspension of these viruses and discovered that the highest dilutions (lowest virus concentrations), rather than killing all the bacteria, formed discrete areas of dead organisms. Counting these areas and multiplying by the dilution factor allowed him to calculate the number of viruses in the original suspension.[21] He realised that he had discovered a new form of virus and later coined the term "bacteriophage".[22][23] Between 1918 and 1921 d'Herelle discovered different types of bacteriophages that could infect several other species of bacteria including Vibrio cholera.[24] Bacteriophages were heralded as a potential treatment for diseases such as typhoid and cholera, but their promise was forgotten with the development of penicillin.[22] Since the early 1970s, bacteria have continued to develop resistance to antibiotics such as penicillin, and this has led to a renewed interest in the use of bacteriophages to treat serious infections.[25]

Early research[edit]

D'Herelle travelled widely to promote the use of bacteriophages in the treatment of bacterial infections. In 1928, he became professor of biology at Yale and founded several research institutes.[26] He was convinced that bacteriophages were viruses despite opposition from established bacteriologists such as the Nobel Prize winner Jules Bordet (1870–1961). Bordet argued that bacteriophages were not viruses but just enzymes released from "lysogenic" bacteria. He said "the invisible world of d'Herelle does not exist".[27] But in the 1930s, the proof that bacteriophages were viruses was provided by Christopher Andrews (1896–1988) and others. They showed that these viruses differed in size and in their chemical and serological properties.

In 1940, the first electron micrograph image of a bacteriophage was published and this silenced sceptics who had argued that bacteriophages were relatively simple enzymes and not viruses.[28] Numerous other types of bacteriophages were quickly discovered and were shown to infect bacteria wherever they are found. But this early research was interrupted by World War II. Even d'Herelle was silenced. Despite his Canadian citizenship, he was interned by the Vichy Government until the end of the war.[29] Knowledge of bacteriophages increased in the 1940s following the formation of the Phage Group by scientists throughout the US. Among the members was Max Delbrück (1906–1981) who founded a course on bacteriophages at Cold Spring Harbor Laboratory.[25] Other key members of the Phage Group included Salvador Luria (1912–1991) and Alfred Hershey (1908–1997). During the 1950s, Hershey and Chase made important discoveries on the replication of DNA during their studies on a bacteriophage called T2. Together with Delbruck they were jointly awarded the 1969 Nobel Prize in Physiology or Medicine "for their discoveries concerning the replication mechanism and the genetic structure of viruses".[30] Since then, the study of bacteriophages has provided insights into the switching on and off of genes, and a useful mechanism for introducing foreign genes into bacteria and many other fundamental mechanisms of molecular biology.[31]

20th century[edit]

By the end of the 19th century, viruses were defined in terms of their infectivity, their ability to be filtered, and their requirement for living hosts. Up until this time, viruses had only been grown in plants and animals, but in 1906, Ross Granville Harrison (1870–1959) invented a method for growing tissue in lymph,[32] and, in 1913, E Steinhardt, C Israeli, and RA Lambert used this method to grow vaccinia virus in fragments of guinea pig corneal tissue.[33] In 1928, HB and MC Maitland grew vaccinia virus in suspensions of minced hens' kidneys.[34] Their method was not widely adopted until the 1950s, when poliovirus was grown on a large scale for vaccine production.[35]

At the turn of the 20th century, evidence for the existence of viruses was obtained from experiments with filters that had pores too small for bacteria to pass through; the term "filterable virus" was coined to describe them.[36] Although the modern concept of a virus was at that time slowly beginning to gain acceptance, the word is ancient. In Latin it means a "slimy liquid, poison offensive odour or taste", and it first appears in the medical literature in the 18th century to describe a poisonous fluid.[37]

Electron micrograph of the rod-shaped particles of tobacco mosaic virus that are too small to be seen using a light microscope

In 1882, Adolf Mayer (1843–1942) described a condition of tobacco plants, which he called "mosaic disease" ("mozaïkziekte"). The diseased plants had variegated leaves that were mottled.[38] He excluded the possibility of a fungal infection and could not detect any bacterium and speculated that a "soluble, enzyme-like infectious principle was involved".[39] He did not pursue his idea any further, and it was the filtration experiments of Ivanovsky and Beijerinck that suggested the cause was a previously unrecognised infectious agent. After tobacco mosaic was recognized as a virus disease, virus infections of many other plants were discovered.[39]

The importance of tobacco mosaic virus in the history of virology cannot be overstated. It was the first virus to be discovered, and the first to be crystallised and its structure shown in detail. The first X-ray diffraction pictures of the crystallised virus were obtained by Bernal and Fankuchen in 1941. On the basis of her pictures, Rosalind Franklin discovered the full DNA structure of the virus in 1955.[40] In the same year, Heinz Fraenkel-Conrat and Robley Williams showed that purified tobacco mosaic virus RNA and its coat protein can assemble by themselves to form functional viruses, suggesting that this simple mechanism was probably the means through which viruses were created within their host cells.[41]

By 1935 many plant diseases were thought to be caused by viruses. In 1922, John Kunkel Small (1869–1938) discovered that insects could act as vectors and transmit virus to plants. In the following decade many diseases of plants were shown to be caused by viruses that were carried by insects and in 1939, Francis Holmes, a pioneer in plant virology,[42] described 129 viruses that caused disease of plants.[43]

A modern electron microscope

Until the 1930s most scientists believed that viruses were small bacteria, but following the invention of the electron microscope in 1938 they were shown to be completely different, to a degree that not all scientists were convinced they were anything other than accumulations of toxic proteins. The situation changed radically when it was discovered that viruses contain genetic material in the form of DNA or RNA.[44] Once they were recognised as distinct biological entities they were soon shown to be the cause of numerous infections of plants, animals, and even of bacteria.[45]

Of the many diseases of humans that were discovered to be caused by viruses in the 20th century only one, smallpox, has been eradicated. Two others – measles and poliomyelitis – could be, but the diseases caused by viruses such as HIV and influenza virus have proved to be more difficult to control.[46] Others diseases, such as those caused by arboviruses, are presenting new challenges.[47]

Late 20th century[edit]

The second half of the 20th century was the golden age of virus discovery and most of the 2,000 recognised species of animal, plant, and bacterial viruses were discovered during these years.[48][49] In 1946, Bovine virus diarrhea was discovered,[50] which is still possibly the commonest pathogen of cattle throughout the world[51] and in 1957, equine arterivirus was discovered.[52] In the 1950s, improvements in virus isolation and detection methods resulted in the discovery of several important human viruses including, Varicella zoster virus,[53] the paramyxoviruses,[54] – which include measles virus,[55] and respiratory syncytial virus[54] – and the rhinoviruses that cause the common cold.[56] In the 1960s more viruses were discovered. In 1963, the hepatitis B virus was discovered by Baruch Blumberg (b. 1925),[57] and in 1965, Howard Temin (1934–1994) described the first retrovirus.[58] Reverse transcriptase, the key enzyme that retroviruses use to translate their RNA into DNA, was first described in 1970, independently by Howard Temin and David Baltimore (b. 1938).[59] This was important to the development of antiviral drugs – a key turning-point in the history of viral infections.[60] In 1983 Luc Montagnier (b. 1932) and his team at the Pasteur Institute in France, first isolated the retrovirus now called HIV.[61] New viruses and strains of viruses were discovered in every decade of the second half of the 20th century. These discoveries have continued in the 21st century as new viral diseases such as SARS[62] and nipah virus[63] have emerged. Despite scientists' achievements over the past one hundred years, viruses continue to pose new threats and challenges.[64]

Table 1. Some of the many viruses that were discovered in the 20th century

Year Virus References
1908 poliovirus [65]
1911 Rous sarcoma virus [66]
1915 bacteriophage of staphylococci [19]
1917 bacteriophage of shigellae [19]
1918 bacteriophage of salmonellae [21]
1927 yellow fever virus [67]
1930 western equine encephalitis virus [68]
1933 eastern equine encephalitis virus [68]
1934 mumps virus [69]
1935 Japanese encephalitis virus [70]
1943 Dengue virus [71]
1949 enteroviruses [72]
1952 Varicella zoster virus [53]
1953 adenovirus [73]
1954 measles virus [55]
1956 paramyxoviruses, rhinovirus [54][56]
1958 monkeypox [74]
1962 rubella virus [75]
1963 hepatitis B virus [76]
1964 Epstein–Barr virus [77]
1965 retroviruses [78]
1966 Lassa fever virus [79]
1967 Marburg virus [80]
1972 norovirus [81]
1973 rotavirus, hepatitis A virus [82][83]
1975 parvovirus B19 [84]
1976 Ebola virus [85]
1980 human T-lymphotropic virus 1 [86]
1982 human T-lymphotropic virus 2 [86]
1983 HIV [87]
1986 human herpesvirus 6 [88]
1989 hepatitis C virus [89]
1990 hepatitis E virus, Human herpesvirus 7 [90]
1994 henipavirus [91]
1997 Anelloviridae [92]

21st century[edit]

As humans have changed their behaviour during the course of history, so have viruses. In ancient times the human population was too small for pandemics to occur and, in the case of some viruses, too small for them to survive. In the 20th and 21st century increasing population densities, revolutionary changes in agriculture and farming methods, and high speed travel have contributed to the spread of new viruses and the re-appearance of old ones.[93][94] Like smallpox, some viral diseases might be conquered, but others, such as SARS will continue to present new challenges.[95] Although vaccines are still the most powerful weapon against viruses, in recent decades antiviral drugs have been developed to specifically target viruses as they replicate in their hosts.[96] The 2009 influenza pandemic showed how rapidly new strains of viruses continue to spread around the world, despite our efforts to contain them.[97] Advances in virus discovery and control continue to be made. Human metapneumovirus, which is a cause of respiratory infections including pneumonia was discovered in 2001.[98] A vaccine for the papillomaviruses that cause cervical cancer was developed between 2002 and 2006.[99] In 2003, the largest virus by far, mimivirus was discovered to infect amoebae.[100] In 2005, human T lymphotropic viruses 3 and 4 were discovered.[101] And, in 2008 the WHO Global Polio Eradication Initiative was re-launched with a plan to eradicate poliomyelitis by 2015.[102]


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