HISTORY OF VIROLOGY

4 Billion Years Ago

On the primeval Earth, the surface of the planet is just cooling and beginning to harden into a crust.

Rain forms pools containing many organic molecules and the first simple life forms appear.

The first viruses also appear. It is not clear where they have come from:

•Regressive evolution - maybe these early viruses are degenerate life-forms which have lost many functions that other organisms possess and have only retained the genetic information essential to their parasitic way of life.

•Cellular origins - perhaps they are sub-cellular, functional assemblies of macromolecules which have escaped their origins inside primitive cells.

•Independent entities - or maybe they just evolved from the self-replicating molecules believed to have existed in the primitive prebiotic 'RNA world' along a parallel course to cellular organisms.

100 Million Years Ago.The Cretaceous Period.

Dinosaurs roam the earth.

The supercontinent Pangaea has begun to break up, but the continents have still not drifted into their present positions.

The climate is much hotter and drier than today.

Way out in space, a BIG meteorite is tumbling towards Earth ...

The Year 3700 BC

The first written record of a virus infection consists of a heiroglyph from Memphis, the capital of ancient Egypt, drawn in approximately 3700 BC, which depicts a temple priest called Ruma (at another place the name is Siptah and it says that it was 1400 BC) showing typical clinical signs of paralytic poliomyelitis .

The Year 1193 BC

The Pharaoh Siptah rules Egypt from 1200-1193 BC when he dies suddenly at the age of about 20.

His mummified body lays undisturbed in his tomb in the Valley of the Kings until 1905 when the tomb was excavated.

The mummy shows that his left leg was withered and his foot was rigidly extended like a horse's hoof - classic paralytic poliomyelitis .

FOOT

The Year 1143 BC

Ramesses V's preserved mummy shows that he died of smallpox at about the age of 35 in 1143 BC.

The pustular lesions on the face of the mummy are very similar to those of more recent patients . However, his head also displays a major wound inflicted either before or shortly after death.

Rabies was one of the Most Feared Diseases of Man

Mesopotamian laws concerning rabid dogs date from 5000-1000 BC. People who let rabid dogs run free were fined. Rabies is known on all continents. Recent epidemics in North America, Europe & India.

Rabies virus causes disease and death in most mammals. Transmitted in nature by foxes, raccoons, skunks and bats to domestic animals.

Dogs and bats transmit to humans.

The Year 1500-1000 BC

Smallpox is endemic in China by 1500-1000BC. In response, the practice of variolation is developed.

Recognizing that survivors of smallpox outbreaks are protected from subsequent infection, variolation involves inhalation of the dried crusts from smallpox lesions like snuff, or in later modifications, inoculation of the pus from a lesion into a scratch on the forearm

The Year 1520Smallpox , which had reached Europe from the East in 710 A.D., was transferred to the Americas by Hernando Cortez.3,500,000 Aztecs died in the next 2 years - effectively the end of the Aztec empire .

Variolation to Control Smallpox arises

Lady Mary Wortley Montagu introduced Variolation to England

Practice of variolation originated in China. Widely used by 1500’s to control smallpox.

Tulipomania in the Late 16th Century Tulips with flower breaking symptoms were prized in Europe and traded for very large sums of money. Tulips were traded with a rage in the 1630’s and speculation began and large fortunes were made. Bulbs were “sold” faster than they could be grown until people realized that bulbs had been sold that did not exist. This lead to panic and the first “Stock Market Crash” in 1637.Traded for One Viceroy Tulip Bulb

4 Tons of Wheat 8 Tons of Rye12 Fat Sheep 8 Fat Pigs2 barrels of butter 8 Fat Oxen2 hogsheads of wine 1 Dress Suit4 barrels of beer 1 Silver Goblet1 Bed with Accessories1000 pounds of Cheese

The Year 1796 On 14th May 1796, Edward Jenner vaccinated an 8 year old boy, James Phipps, with material from a cowpox lesion on the hand of a milkmaid, Sarah Nelmes.James, who had never had smallpox , developed a small lesion at the site of vaccination which healed in 2 weeks.On 1st July 1796, Jenner challenged the boy by deliberately inoculating him with material from a real case of smallpox !

The Development of Rabies Vaccine

100 years later - Louis Pasteur tested a rabies vaccine. This depended on deliberate, experimental production of the vaccine by serial passage of infectious virus in rabbit spinal cords.

The next vaccines for yellow fever and influenza did not appear until the 1930s.

Adolph Mayer-1883. Inoculated plants with agent that he named Tobacco mosaic virus. Showed that the agent was soluble and could not be grown in culture. Thought that the pathogen might be a small bacterium.

Birth of virology

The Year 1886

John Buist (a Scottish pathologist) stained lymph from skin lesions of a smallpox patient and saw "elementary bodies" which he thought were the spores of micrococci.

These were in fact smallpox virus particles - just large enough to see with the light microscope.

The Year 1892 On 12th February, Dmitri Iwanowski, a Russian botanist, presents a paper to the St. Petersburg Academy of Science which shows that extracts from diseased tobacco plants can transmit disease to other plants after passage through ceramic filters fine enough to retain the smallest known bacteria.

This is generally recognised as the beginning of Virology. Unfortunately, neither Iwanowski nor the scientific community fully realize the significance of these results.

The Birth of Virology

Found that the agent could reproduce only in the host and was not inactivated by alcohol. Called the agent a “contagium vivum fluidum” or a “contagious living liquid”. Clearly stated that the agent was not a bacterium, fungus or other culturable pathogen. He is known as the “Father of Virology”.

Martinus Beijerinck-1897

F.A.J. Loeffler (left) and P. Frosch working in 1898 with Robert Kosch (right) in Germany discovered the first vertebrate virus, foot-and-mouth disease virus, with filters that held back bacteria.

Proof that Animal Diseases can be Caused by Viruses

Walter Reed (1900) showed that yellow fever in humans was caused by a filterable virus that was transmitted by mosquitoesEllerman and Bang (1908) demonstrated that leukemia in chickens was caused by a virus

Walter Reed (1851-1902)

During the Spanish-American War & subsequent building of the Panama Canal, American deaths due to yellow fever were colossal. The disease also appeared to be spreading slowly northward into the continental United States.

Through experimental transmission to mice, in 1900 Walter Reed demonstrated that yellow fever was caused by a virus, spread by mosquitoes.

Karl Landsteiner (1868-1943)

Karl Landsteiner (1868-1943) and Erwin Popper proved that poliomyelitis was caused by a virus. Landsteiner and Popper were the first to prove that viruses could infect humans as well as animals.

Francis Peyton Rous (1879-1970)

Francis Peyton Rous (1879-1970) demonstrated in (1911) that a virus (Rous sarcoma virus) can cause cancer in chickens. (For this work, he was eventually awarded the Nobel Prize, in 1962 at age 84.

Rous is the first person to show that a virus could cause cancer in animals (see also 1981).

Felix d'Herelle (1873-1949)

Following Frederick Twort's work, Felix d'Herelle independently recognizes viruses which infect bacteria, which he called bacteriophages (eaters of bacteria).

The discovery of bacteriophages provided an invaluable opportunity to study virus replication at a time prior to the development of cell culture when the only way to study viruses was by infecting whole organisms.

Wendell Stanley (1887-1955)

Wendell Stanley (1887-1955) crystallizeed tobacco mosaic virus (TMV) and showed that it remains infectious (Nobel Prize, 1946).

Stanley's work is the first step towards describing the molecular structure of any virus and helps to further illuminate the nature of viruses.

Max Theiler (1899-1972)

Max Theiler was the first to propagate yellow fever virus in chick embryos and successfully produced an attenuated vaccine - the 17D strain. Theiler's vaccine was so safe and effective that it is still in use today!

This work saved millions of lives and set the model for the production of many subsequent vaccines. For this work, Theiler was awarded the Nobel Prize in 1951.

The Year 1939

Emory Ellis (1906-) and Max Delbrück (1906-1981)

Established the concept of the "one step virus growth cycle" essential to the understanding of virus replication.This work laid the basis for the understanding of virus replication - that virus particles do not "grow" but are instead assembled from preformed components.

The Year 1941

George Hirst demonstrated that influenza virus agglutinates red blood cells. This was the first rapid, quantitative method of measuring eukaryotic viruses. Now viruses could be counted!

The Year 1945

Salvador Luria (1912-1991)

Alfred Hershey

(1908-1997)

Salvador Luria (1912-1991) and Alfred Hershey (1908-

1997) demonstrated that bacteriophages mutate. (Nobel

Prize, 1969)This work proves that similar

genetic mechanisms operate in viruses as in cellular organisms

and lays the basis for the understanding of antigenic

variation in viruses.

The Year 1949

John Enders (1897-1985)

Thomas Weller (1915–) Frederick Robbins (1916–)

John Enders, Thomas Weller (1915–) and Frederick Robbins (1916–) were able to grow poliovirus in vitro using human

tissue culture. (Nobel Prize, 1954) This development led to the isolation of many new viruses in tissue culture.

The Year 1950 André Lwoff (1902-1994) Louis Siminovitch and Niels Kjeldgaard discovered lysogenic bacteriophages in Bacillus megaterium irradiated with ultra-violet light and coined the term prophage. (Nobel Prize, 1965).

Although the concept of lysogeny had been around since the 1920s, this work clarified the existence of temperate and virulent bacteriophages and led to subsequent studies concerning the control of gene expression in prokaryotes, resulting ultimately in the operon hypothesis of Jacob and Monod.

Also in 1950, the World Health Organization proposed a programme to eradicate smallpox from the Americas. This was acheived in 8 years.

The Year 1952 Renato Dulbecco (1914-) showed that animal viruses can form plaques in a similar way to bacteriophages. (Nobel Prize, 1975) Dulbecco's work allowed rapid quantitation of animal viruses using assays which had only previously been possible with bacteriophages.

Alfred Hershey (1908-1997) and Martha Chase demonstrated that DNA was the genetic material of a bacteriophage. Although the initial evidence for DNA as the molecular basis of genetic inheritance was discovered using a bacteriophage, this principle of course applies to all cellular organisms (though not all viruses!).

The Year 1957 Heinz Fraenkel-Conrat (1910-1999) and R.C. Williams showed that when mixtures of purified tobacco mosaic virus (TMV) RNA and coat protein were incubated together, virus particles formed spontaneously. The discovery that virus particles could form spontaneously from purified subunits without any extraneous information indicated that the particle was in the free energy minimum state and was therefore the favoured structure of the components. This stability is an important feature of virus particles.

Alick Isaacs and Jean Lindemann discovered interferon. Although the initial hopes for interferons as broad spectrum antiviral agents equivalent to antibiotics have faded, interferons were the first cytokines to be studied in detail.

The Year 1963

Baruch Blumberg discovers hepatitis B virus (HBV). (Nobel Prize, 1976) Blumberg went on to develop the first vaccine against the HBV, considered by some to be the first vaccine against cancer because of the strong association of hepatitis B with liver cancer.

The Year 1970

Howard Temin (1934-1994) and David Baltimore independently discovered reverse transcriptase in retroviruses. (Nobel Prize, 1975).The discovery of reverse transcription established a pathway for genetic information flow from RNA to DNA, refuting the so-call "central dogma" of molecular biology.

Year 1973

Peter Doherty and Rolf Zinkernagl demonstrate the basis of antigenic recognition by the cellular immune system. (Nobel Prize, 1996) The demonstration that lymphocytes recognize both virus antigens and major histocompatibility antigens in order to kill virus-infected cells established the specificity of the cellular immune system.

Year 1976

J. Michael Bishop and Harold Varmus discover that the oncogene from Rous sarcoma virus is also found in the cells of normal animals, including humans (Nobel Prize, 1989).

Proto-oncogenes are essential for normal development but can become cancer genes when cellular regulators are damaged or modified, e.g. by virus transduction.

Year 1983

Luc Montaigner and Robert Gallo announced the discovery of human immunodeficiency virus (HIV), the causative agent of AIDS.In only two years since the start of the AIDS epidemic the agent responsible has been identified.

Year 1999

Nucleotide sequence of the largest virus genome yet known completed: Paramecium bursaria Chlorella virus 1.

Year 2001

The complete nucleotide sequence of the human genome is published.

About 11% of the human genome is composed of retrovirus-like retrotransposons: "transposable elements in which transposition involves a process of reverse transcription with an RNA intermediate similar to that of a retrovirus".

WHERE WE STOOD IN 2005: PREVENTING, CONTROLING AND CURING VIRAL DISEASES

Polio: Hopefully will soon be the second viral disease wiped out.

Hepatitis B: An effective world wide vaccination strategy is being implemented. But liver cancer deaths caused by viral infection will

continue for many decades.

Measles: Good vaccine since 1963; this disease could be eliminated with a world-wide effort.

Influenza: Effective strain-specific vaccines are generated each year, but new variant and potentially dangerous strains emerge each year.

HIV: No vaccine; drugs are somewhat effective but are costly and toxic. Drug resistance quickly appears. World-wide sexual spread continues. More than 50 million people have been infected so far.

SARS: Vaccines are being developed; easy transmission to humans but outbreaks controllable quarantining patents in hospitals coupled with stringent monitoring of all potential contacts.

We all share the world and our bodies with numerous viruses that cause hepatitis, respiratory disease, mononucleosis, diarrhea,

genital warts, herpes, and some forms of cancer.

Over the past 10 years: As the global HIV epidemic continues, sporadic cases and outbreaks in humans of some non-human host viruses such as Ebola, Hanta, SARS and many other viruses raise

concerns about future epidemics by other viruses in the new century.

FourCorners Virus (Hanta)

Over the last 5 years: H5N1 avian influenza virus continues to sporadically infect humans in Southeast Asia and elsewhere, and this year an H1N1 flu strain emerged and spread rapidly across the globe

Plant viruses: Emerging diseases include High Plains Virus, Grapevine Leafroll associated virus, Potato virus Y, geminiviruses. Plum pox virus, which has decimated stone fruit trees in Europe since the early 1900s, has now spread to the United States and Canada

BillionsBillions

World Population Growth Through HistoryWorld Population Growth Through History

Continued Emergence of New Viruses is Almost Certain

Climate change could have positive, negative or no impact on individual plant diseases. More research is needed to obtain base-line information on different disease systems. Most plant disease models use different climatic variables and operate at a different spatial and temporal scale than do the global climate models. Improvements in methodology are necessary to realistically assess disease impacts at a global scale

Aphid populations are exploding because of warmer winters, according to scientists from Rothamsted Research. The scientists have been monitoring the flying form of all aphid species in the United Kingdom for 42 years. This year, the first aphid was caught almost four weeks ahead of the 42-year average. The peach-potato aphid (Myzus persicae), one of UK’s most damaging aphids, has been found to be flying two weeks earlier for every 1°C rise in the average temperature.