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4.12.3: RNA Oncogenic Viruses - Biology

4.12.3: RNA Oncogenic Viruses - Biology


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An estimated 15% of all human cancers worldwide may be attributed to viruses.

Learning Objectives

  • Classify the viruses with oncogenic properties

Key Points

  • Both DNA and RNA viruses have been shown to be capable of causing cancer in humans.
  • Human T lymphotrophic virus type 1 and hepatitis C viruses are the two RNA viruses that contribute to human cancers.
  • Hepatitis C virus is an enveloped RNA virus capable of causing acute and chronic hepatitis in humans by infecting liver cells. It is estimated 3% of the world’s population are carriers. Chronic infection with hepatitis C virus results in cirrhosis, which in turn can lead to liver cancer.

Key Terms

  • oncogenic: Tending to cause the formation of tumors.
  • hepatocellular: Of or pertaining to the cells of the liver

There are two classes of cancer viruses: DNA and RNA viruses. Several viruses have been linked to certain types of cancer in humans. These viruses have varying ways of reproduction and represent several different virus families. Specifically, RNA viruses have RNA as their genetic material and can be either single-stranded RNA (ssRNA) or double-stranded (dsRNA). RNA viruses are classified based on the Baltimore classification system and do not take into account viruses with DNA intermediates in their life cycle. Viruses which contain RNA for their genetic material but do include DNA intermediates in their life cycle are called “retroviruses. ” There are numerous RNA oncogenic viruses that have been linked to various cancer types. These various oncogenic viruses include:

1. Human T lymphotrophic virus type 1 (HTLV-I), a retrovirus, has been linked to T-cell leukemia. 2. The hepatitis C virus has been linked to liver cancer in people with chronic infections.

2. Hepatitis viruses includes hepatitis B and hepatitis C have been linked to hepatocellular carcinoma.

3. Human papillomaviruses (HPV) have been linked to cancer of the cervix, anus, penis, vagina/vulva, and some cancers of the head and neck.

4. Kaposi’s sarcoma-associated herpesvirus (HHV-8) has been linked to Kaposi’s sarcoma and primary effusion lymphoma.

5. Epstein-Barr virus (EBV) has been linked to Burkitt’s lymphoma, Hodgkin’s lymphoma, post-transplantation lymphoproliferative disease, and nasopharyngeal carcinoma.

RNA Retroviruses

Retroviruses are different from DNA tumor viruses in that their genome is RNA, but they are similar to many DNA tumor viruses in that the genome is integrated into host genome. Since RNA makes up the genome of the mature virus particle, it must be copied to DNA prior to integration into the host cell chromosome. This lifestyle goes against the central dogma of molecular biology in which that DNA is copied into RNA. The outer envelope comes from the host cell plasma membrane. Coat proteins (surface antigens) are encoded by env (envelope) gene and are glycosylated. One primary gene product is made, but this is cleaved so that there are more than one surface glycoprotein in the mature virus (cleavage is by host enzyme in the Golgi apparatus). The primary protein (before cleavage) is made on ribosomes attached to the endoplasmic reticulum and is a transmembrane (type 1) protein. Inside the membrane is an icosahedral capsid containing proteins encoded by the gag gene (group-specific AntiGen). Gag-encoded proteins also coat the genomic RNA. Again, there is one primary gene product. This is cleaved by a virally-encoded protease (from the pol gene). There are two molecules of genomic RNA per virus particle with a 5′ cap and a 3′ poly A sequence. Thus, the virus is diploid. The RNA is plus sense (same sense as mRNA). About 10 copies of reverse transcriptase are present within the mature virus, these are encoded by the pol gene. Pol gene codes for several functions (again, as with gag and env, a polyprotein is made that is then cut up).


Virus

The existence of submicroscopic infectious agents was suspected by the end of the 19th cent. in 1892 the Russian botanist Dimitri Iwanowski showed that the sap from tobacco plants infected with mosaic disease, even after being passed through a porcelain filter known to retain all bacteria, contained an agent that could infect other tobacco plants. In 1900 a similarly filterable agent was reported for foot-and-mouth disease foot-and-mouth disease
or hoof-and-mouth disease,
highly contagious disease almost exclusive to cattle, sheep, swine, goats, and other cloven-hoofed animals. It is caused by a virus, specifically an aphthovirus, that was identified in 1897.
. Click the link for more information. of cattle. In 1935 the American virologist W. M. Stanley Stanley, William Meredith,
1904󈞳, American biochemist, b. Ridgeville, Ind., Ph.D. Univ. of Illinois, 1929. He was a professor at the Rockefeller Institute for Medical Research (now Rockefeller Univ.) from 1932 to 1948 and at the Univ.
. Click the link for more information. crystallized tobacco mosaic virus for that work Stanley shared the 1946 Nobel Prize in Chemistry. Later studies of virus crystals established that the crystals were composed of individual virus particles, or virions. By the early 21st cent. the understanding of viruses had grown to the point where scientists synthesized (2002) a strain of poliovirus using their knowledge of that virus's genetic code and chemical components required.

Viral Structure

Typically the protein coat, or capsid, of an individual virus particle, or virion, is composed of multiple copies of one or several types of protein subunits, or capsomeres. Some viruses contain enzymes, and some have an outer membranous envelope. Many viruses have striking geometrically regular shapes, with helical structure as in tobacco mosaic virus, polyhedral (often icosahedral) symmetry as in herpes virus, or more complex mixtures of arrangements as in large viruses, such as the pox viruses and the larger bacterial viruses, or bacteriophages bacteriophage
, virus that infects bacteria and sometimes destroys them by lysis, or dissolution of the cell. Bacteriophages, or phages, have a head composed of protein, an inner core of nucleic acid&mdasheither deoxyribonucleic acid (DNA) or ribonucleic acid (RNA)&mdashand a
. Click the link for more information. . Certain viruses, such as bacteriophages, have complex protein tails. The inner viral genetic material&mdashthe nucleic acid&mdashmay be double stranded, with two complementary strands, or single stranded it may be deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). The nucleic acid specifies information for the synthesis of from a few to 50 different proteins, depending on the type of virus.

Viral Infection of a Host Cell

A free virus particle may be thought of as a packaging device by which viral genetic material can be introduced into appropriate host cells, which the virus can recognize by means of proteins on its outermost surface. A bacterial virus infects the cell by attaching fibers of its protein tail to a specific receptor site on the bacterial cell wall and then injecting the nucleic acid into the host, leaving the empty capsid outside. In viruses with a membrane envelope the nucleocapsid (capsid plus nucleic acid) enters the cell cytoplasm by a process in which the viral envelope merges with a host cell membrane, often the membrane delimiting an endocytic structure (see endocytosis endocytosis
, in biology, process by which substances are taken into the cell. When the cell membrane comes into contact with a suitable food, a portion of the cell cytoplasm surges forward to meet and surround the material and a depression forms within the cell wall.
. Click the link for more information. ) in which the virus has been engulfed.

Within the cell the virus nucleic acid uses the host machinery to make copies of the viral nucleic acid as well as enzymes needed by the virus and coats and enveloping proteins, the coat proteins of the virus. The details of the process by which the information in viral nucleic acid is expressed and the sites in the cell where the virus locates vary according to the type of nucleic acid the virus contains and other viral features. As viral components are formed within a host cell, virions are created by a self-assembly process that is, capsomere subunits spontaneously assemble into a protein coat around the nucleic core. Release of virus particles from the host may occur by lysis of the host cell, as in bacteria, or by budding from the host cell's surface that provides the envelope of membrane-enveloped forms.

Some viruses do not kill host cells but rather persist within them in one form or another. For example, certain of the viruses that can transform cells into a cancerous state (see cancer cancer,
in medicine, common term for neoplasms, or tumors, that are malignant. Like benign tumors, malignant tumors do not respond to body mechanisms that limit cell growth.
. Click the link for more information. ) are retroviruses their genetic material is RNA but they carry an enzyme that can copy the RNA's information into DNA molecules, which then can integrate into the genetic apparatus of the host cell and reside there, generating corresponding products via host cell machinery (see also retrovirus retrovirus,
type of RNA virus that, unlike other RNA viruses, reproduces by transcribing itself into DNA. An enzyme called reverse transcriptase allows a retrovirus's RNA to act as the template for this RNA-to-DNA transcription.
. Click the link for more information. ). Similarly, in bacterial DNA viruses known as temperate phages, the viral nucleic acid becomes integrated into the host cell chromosomal material, a condition known as lysogeny lysogenic phages are similar in many ways to genetic particles in bacterial cells called episomes episome
, unit of genetic material composed of a series of genes that sometimes has an independent existence in a host cell and at other times is integrated into a chromosome of the cell, replicating itself along with the chromosome. Episomes have been studied in bacteria.
. Click the link for more information. (see recombination recombination,
process of "shuffling" of genes by which new combinations can be generated. In recombination through sexual reproduction, the offspring's complete set of genes differs from that of either parent, being rather a combination of genes from both parents.
. Click the link for more information. ).

Viral Diseases

Some human diseases are apparently caused by the body's response to virus infection: immune reaction to altered virus-infected cells, release by infected cells of inflammatory substances, or circulation in the body of virus-antibody complexes are all virus-caused immunological disorders. Viruses cause many diseases of economically important animals and plants, some transmitted by carriers such as insects. A retrovirus (HIV HIV,
human immunodeficiency virus, either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States.
. Click the link for more information. ) causes AIDS AIDS
or acquired immunodeficiency syndrome,
fatal disease caused by a rapidly mutating retrovirus that attacks the immune system and leaves the victim vulnerable to infections, malignancies, and neurological disorders. It was first recognized as a disease in 1981.
. Click the link for more information. , several viruses (e.g. Epstein-Barr virus Epstein-Barr virus
(EBV), herpesvirus that is the major cause of infectious mononucleosis and is associated with a number of cancers, particularly lymphomas in immunosuppressed persons, including persons with AIDS.
. Click the link for more information. , human papillomavirus human papillomavirus
(HPV), any of a family of more than 100 viruses that cause various growths, including plantar warts and genital warts, a sexually transmitted disease. Genital warts, sometimes called condylomata acuminata, are soft and often occur in clusters.
. Click the link for more information. ) cause particular forms of cancer in humans, and many have been shown to cause tumors in animals. Other viruses that infect humans cause measles measles
or rubeola
, highly contagious disease typically contracted during childhood, caused by a filterable virus and spread by droplet spray from the nose, mouth, and throat of individuals in the infective stage.
. Click the link for more information. , mumps mumps
(epidemic parotitis), acute contagious viral disease, manifesting itself chiefly in pain and swelling of the salivary glands, especially those at the angle of the jaw. Other symptoms are fever, a general feeling of illness, and pain on chewing or swallowing.
. Click the link for more information. , smallpox smallpox,
acute, highly contagious disease causing a high fever and successive stages of severe skin eruptions. Occurring worldwide in epidemics, it killed up to 40% of those who contracted it and accounted for more deaths over time than any other infectious disease.
. Click the link for more information. , yellow fever yellow fever,
acute infectious disease endemic in tropical Africa and many areas of South and Central America. Yellow fever is caused by a virus transmitted by the bite of the female Aedes aegypti mosquito, which breeds in stagnant water near human habitations.
. Click the link for more information. , rabies rabies
or hydrophobia
, acute viral infection of the central nervous system in dogs, bats, foxes, raccoons, skunks, and other animals, and in humans. The virus is transmitted from an animal to a person, or from one animal to another, via infected saliva, most often by
. Click the link for more information. , poliomyelitis poliomyelitis
, polio,
or infantile paralysis,
acute viral infection, mainly of children but also affecting older persons. Historically, there were three immunologic types of poliomyelitis virus, but two of three types of the wild virus have been eradicated
. Click the link for more information. , influenza influenza
or flu,
acute, highly contagious disease caused by a RNA virus (family Orthomyxoviridae) formerly known as the grippe. There are three types of the virus, designated A, B, and C, but only types A and B cause more serious contagious infections.
. Click the link for more information. , and the common cold cold, common,
acute viral infection of the mucous membranes of the nose and throat, often involving the sinuses. The typical sore throat, sneezing, and fatigue may be accompanied by body aches, headache, low fever, and chills.
. Click the link for more information. .

The techniques of molecular biology and genetic engineering have made possible the development of antiviral drugs antiviral drug,
any of several drugs used to treat viral infections. The drugs act by interfering with a virus's ability to enter a host cell and replicate itself with the host cell's DNA.
. Click the link for more information. effective against a variety of viral infections. Viruses, like bacterial infective agents, act as antigens in the body and elicit the formation of antibodies antibody,
protein produced by the immune system (see immunity) in response to the presence in the body of antigens: foreign proteins or polysaccharides such as bacteria, bacterial toxins, viruses, or other cells or proteins.
. Click the link for more information. in an infected individual (see immunity immunity,
ability of an organism to resist disease by identifying and destroying foreign substances or organisms. Although all animals have some immune capabilities, little is known about nonmammalian immunity.
. Click the link for more information. ). Indeed, vaccines against viral diseases such as smallpox were developed before the causative agents were known. Some viruses stimulate cellular production of interferon interferon
, any of a group of proteins produced by cells in the body in response to an attack by a virus. A cell infected by a virus releases minute amounts of interferons, which attach themselves to neighboring cells, prompting them to start producing their own protective
. Click the link for more information. , which inhibits viral growth within the infected cell.

Classification

Viruses are not usually classified into conventional taxonomic groups but are usually grouped according to such properties as size and shape, the virus's chemical composition and genome, and the method by which the virus reproduces. These features include the type of nucleic acid a virus contains, DNA or RNA, whether the virus is single- or double-stranded, and the structure of the capsid and the number of protein subunits in it. It has been estimated by virologists, based on the number species of living things that viruses might infect, that there could be as many as 200 million viruses, or perhaps many more, but less than 10,000 viruses have been named and classified.

Bibliography

See C. Zimmer, A Planet of Viruses (2011).


Hepatitis B virus molecular biology and pathogenesis

As obligate intracellular parasites, viruses need a host cell to provide a milieu favorable to viral replication. Consequently, viruses often adopt mechanisms to subvert host cellular signaling processes. While beneficial for the viral replication cycle, virus-induced deregulation of host cellular signaling processes can be detrimental to host cell physiology and can lead to virus-associated pathogenesis, including, for oncogenic viruses, cell transformation and cancer progression. Included among these oncogenic viruses is the hepatitis B virus (HBV). Despite the availability of an HBV vaccine, 350-500 million people worldwide are chronically infected with HBV, and a significant number of these chronically infected individuals will develop hepatocellular carcinoma (HCC). Epidemiological studies indicate that chronic infection with HBV is the leading risk factor for the development of HCC. Globally, HCC is the second highest cause of cancer-associated deaths, underscoring the need for understanding mechanisms that regulate HBV replication and the development of HBV-associated HCC. HBV is the prototype member of the Hepadnaviridae family members of this family of viruses have a narrow host range and predominately infect hepatocytes in their respective hosts. The extremely small and compact hepadnaviral genome, the unique arrangement of open reading frames, and a replication strategy utilizing reverse transcription of an RNA intermediate to generate the DNA genome are distinguishing features of the Hepadnaviridae. In this review, we provide a comprehensive description of HBV biology, summarize the model systems used for studying HBV infections, and highlight potential mechanisms that link a chronic HBV-infection to the development of HCC. For example, the HBV X protein (HBx), a key regulatory HBV protein that is important for HBV replication, is thought to play a cofactor role in the development of HBV-induced HCC, and we highlight the functions of HBx that may contribute to the development of HBV-associated HCC.

Keywords: Hepatitis B virus hepatitis B virus life cycle hepatitis B virus-associated disease hepatocellular carcinoma.

Conflict of interest statement

There are no conflicts of interest.

Figures

Molecular biology of hepatitis B…

Molecular biology of hepatitis B virus (HBV). (A) Scaled depiction of the HBV…

Life cycle of hepatitis B…

Life cycle of hepatitis B virus (HBV). Mature HBV virions enter hepatocytes through…

The natural history of an…

The natural history of an hepatitis B virus (HBV) infection. Infection with HBV…


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Oncogenic Viruses in Skull Base Chordomas

Background: Chordomas are rare tumors assumed to derive from notochordal remnants. We believe that a molecular switch is responsible for their malignant behavior. The involvement of oncogenic viruses has not been studied, however. Thus, in the present study, we investigated the presence of oncogenic viruses in chordomas.

Methods: DNA and RNA from snap-frozen chordoma (n = 18) and chondrosarcoma (n = 15) specimens were isolated. Real-time PCR or RT-PCR was performed to assess the presence of multiple oncogenic viruses, including herpesviridea (herpes simplex virus [HSV]-1, HSV-2, Epstein-Barr virus [EBV], cytomegalovirus, human herpesvirus [HHV]- 6, HHV-7, and Kaposi's sarcoma-associated herpesvirus), polyomaviridea (parvovirus B19 [PVB19], BK virus, JC virus, Simian virus 40, Merkel cell polyomavirus, human polyomavirus [HPyV]-6, and HPyV-7), papillomaviridae, and respiratory viruses. Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to validate the positive results.

Results: PVB19 DNA was detected in 4 of 18 chordomas (22%) and in 1 of 15 chondrosarcomas (7%). IHC recognizing the VP2 capsid protein of PVB19 showed a positive cytoplasmic staining in 44% of the cases (14 of 32). HHV7 DNA was present in 6 of the 18 chordomas (33%). Genomic DNA of EBV was found in 22% of the samples however, no positive results were found on ISH. None of the chordoma cases showed any presence of DNA from the remaining viruses.

Conclusions: Viral involvement in the etiology of chordomas is likely, with PVB19 the most distinguishing.

Keywords: Cancer Chondrosarcoma Chordoma Oncogenic virus PVB19 Virus.


Explained: Why RNA vaccines for Covid-19 raced to the front of the pack

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Developing and testing a new vaccine typically takes at least 12 to 18 months. However, just over 10 months after the genetic sequence of the SARS-CoV-2 virus was published, two pharmaceutical companies applied for FDA emergency use authorization of vaccines that appear to be highly effective against the virus.

Both vaccines are made from messenger RNA, the molecule that cells naturally use to carry DNA’s instructions to cells’ protein-building machinery. A vaccine based on mRNA has never been approved by the FDA before. However, many years of research have gone into RNA vaccines, which is one reason why scientists were able to start testing such vaccines against Covid-19 so quickly. Once the viral sequences were revealed in January, it took just days for pharmaceutical companies Moderna and Pfizer, along with its German partner BioNTech, to generate mRNA vaccine candidates.

“What’s particularly unique to mRNA is the ability to rapidly generate vaccines against new diseases. That I think is one of the most exciting stories behind this technology,” says Daniel Anderson, a professor of chemical engineering at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.

Most traditional vaccines consist of either killed or weakened forms of a virus or bacterium. These provoke an immune response that allows the body to fight off the actual pathogen later on.

Instead of delivering a virus or a viral protein, RNA vaccines deliver genetic information that allows the body’s own cells to produce a viral protein. Synthetic mRNA that encodes a viral protein can borrow this machinery to produce many copies of the protein. These proteins stimulate the immune system to mount a response, without posing any risk of infection.

A key advantage of mRNA is that it is very easy to synthesize once researchers know the sequence of the viral protein they want to target. Most vaccines for SARS-CoV-2 provoke an immune response that targets the coronavirus spike protein, which is found on the surface of the virus and gives the virus its characteristic spiky shape. Messenger RNA vaccines encode segments of the spike protein, and those mRNA sequences are much easier to generate in the lab than the spike protein itself.

“With traditional vaccines, you have to do a lot of development. You need a big factory to make the protein, or the virus, and it takes a long time to grow them,” says Robert Langer, the David H. Koch Institute Professor at MIT, a member of the Koch Institute, and one of the founders of Moderna. “The beauty of mRNA is that you don’t need that. If you inject nanoencapsulated mRNA into a person, it goes into the cells, and then the body is your factory. The body takes care of everything else from there.”

Langer has spent decades developing novel ways to deliver medicines, including therapeutic nucleic acids such as RNA and DNA. In the 1970s, he published the first study showing that it was possible to encapsulate nucleic acids, as well as other large molecules, in tiny particles and deliver them into the body. (Work by MIT Institute Professor Phillip Sharp and others on RNA splicing, which also laid groundwork for today’s mRNA vaccines, began in the ’70s as well.)

“It was very controversial at the time,” Langer recalls. “Everybody told us it was impossible, and my first nine grants were rejected. I spent about two years working on it, and I found over 200 ways to get it to not work. But then eventually I did find a way to get it to work.”

That paper, which appeared in Nature in 1976, showed that tiny particles made of synthetic polymers could safely carry and slowly release large molecules such as proteins and nucleic acids. Later, Langer and others showed that when polyethylene glycol (PEG) was added to the surface of nanoparticles, they could last in the body for much longer, instead of being destroyed almost immediately.

In subsequent years, Langer, Anderson, and others have developed fatty molecules called lipid nanoparticles that are also very effective at delivering nucleic acids. These carriers protect RNA from being broken down in the body and help to ferry it through cell membranes. Both the Moderna and Pfizer RNA vaccines are carried by lipid nanoparticles with PEG.

“Messenger RNA is a large hydrophilic molecule. It doesn’t naturally enter cells by itself, and so these vaccines are wrapped up in nanoparticles that facilitate their delivery inside of cells. This allows the RNA to be delivered inside of cells, and then translated into proteins,” Anderson says.

In 2018, the FDA approved the first lipid nanoparticle carrier for RNA, which was developed by Alnylam Pharmaceuticals to deliver a type of RNA called siRNA. Unlike mRNA, siRNA silences its target genes, which can benefit patients by turning off mutated genes that cause disease.

One drawback to mRNA vaccines is that they can break down at high temperatures, which is why the current vaccines are stored at such cold temperatures. Pfizer’s SARS-CoV-2 vaccine has to be stored at -70 degrees Celsius (-94 degrees Fahrenheit), and the Moderna vaccine at -20 C (-4 F). One way to make RNA vaccines more stable, Anderson points out, is to add stabilizers and remove water from the vaccine through a process called lyophilization, which has been shown to allow some mRNA vaccines to be stored in a refrigerator instead of a freezer.

The striking effectiveness of both of these Covid-19 vaccines in phase 3 clinical trials (roughly 95 percent) offers hope that not only will those vaccines help to end the current pandemic, but also that in the future, RNA vaccines may help in the fight against other diseases such as HIV and cancer, Anderson says.

“People in the field, including myself, saw a lot of promise in the technology, but you don’t really know until you get human data. So to see that level of protection, not just with the Pfizer vaccine but also with Moderna, really validates the potential of the technology — not only for Covid, but also for all these other diseases that people are working on,” he says. “I think it’s an important moment for the field.”


Contents

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 1876, Adolf Mayer, who directed the Agricultural Experimental Station in Wageningen, was the first to show that what he called "Tobacco Mosaic Disease" was infectious. He thought that it was caused by either a toxin or a very small bacterium. Later, in 1892, the Russian biologist Dmitry Ivanovsky (1864–1920) used a Chamberland 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), a microbiology teacher at the Agricultural School in Wageningen repeated experiments by Adolf Mayer and became convinced that filtrate 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 that they were in fact, particles. [3] In the same year, 1898, 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]

The first human virus to be identified was the yellow fever virus. [6] In 1881, Carlos Finlay (1833–1915), a Cuban physician, first conducted and published research that indicated that mosquitoes were carrying the cause of yellow fever, [7] a theory proved in 1900 by commission headed 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. [8] Gorgas later organised the elimination of the mosquitoes from Panama, which allowed the Panama Canal to be opened in 1914. [9] The virus was finally isolated by Max Theiler (1899–1972) in 1932 who went on to develop a successful vaccine. [10]

By 1928 enough was known about viruses to enable the publication of Filterable Viruses, a collection of essays covering all known viruses edited by Thomas Milton Rivers (1888–1962). Rivers, a survivor of typhoid fever contracted at the age of twelve, went on to have a distinguished career in virology. 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." [11]

The notion 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, though he had probably observed clumps of vaccinia. [12] 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), [13] that virus particles, especially bacteriophages, were shown to have complex structures. 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. [14]

In 1935, Wendell Stanley examined the tobacco mosaic virus and found it was mostly made of protein. [15] In 1939, Stanley and Max Lauffer (1914) separated the virus into protein and nucleic acid, [16] which was shown by Stanley's postdoctoral fellow Hubert S. Loring to be specifically RNA. [17] 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. [18]

In Pasteur's day, and for many years after his death, the word "virus" was used to describe any cause of infectious disease. Many bacteriologists soon discovered the cause of numerous infections. However, some infections remained, many of them horrendous, for which no bacterial cause could be found. These agents were invisible and could only be grown in living animals. The discovery of viruses paved the way to understanding 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. [19]

Discovery Edit

Bacteriophages are the viruses that infect and replicate in bacteria. They were discovered in the early 20th century, by the English bacteriologist Frederick Twort (1877–1950). [20] 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 cholerae – the cause of cholera. The agent in the water could be passed through filters that remove bacteria but was destroyed by boiling. [21] 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. [20] He proposed that the agent might be "an amoeba, an ultramicroscopic virus, a living protoplasm, or an enzyme with the power of growth". [21]

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. [20] 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. [22] He realised that he had discovered a new form of virus and later coined the term "bacteriophage". [23] [24] Between 1918 and 1921 d'Herelle discovered different types of bacteriophages that could infect several other species of bacteria including Vibrio cholerae. [25] Bacteriophages were heralded as a potential treatment for diseases such as typhoid and cholera, but their promise was forgotten with the development of penicillin. [23] 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. [26]

Early research 1920–1940 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. [27] 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". [28] But in the 1930s, the proof that bacteriophages were viruses was provided by Christopher Andrewes (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 of a bacteriophage was published and this silenced sceptics who had argued that bacteriophages were relatively simple enzymes and not viruses. [29] Numerous other types of bacteriophages were quickly discovered and were shown to infect bacteria wherever they are found. Early research was interrupted by World War II. d'Herelle, despite his Canadian citizenship, was interned by the Vichy Government until the end of the war. [30]

Modern era Edit

Knowledge of bacteriophages increased in the 1940s following the formation of the Phage Group by scientists throughout the US. Among the members were Max Delbrück (1906–1981) who founded a course on bacteriophages at Cold Spring Harbor Laboratory. [26] 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". [31] 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. [32]

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. [33] 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". [34] 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. [34]

The importance of tobacco mosaic virus in the history of viruses 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 structure of the virus in 1955. [35] 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. [36]

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, [37] described 129 viruses that caused disease of plants. [38] Modern, intensive agriculture provides a rich environment for many plant viruses. In 1948, in Kansas, US, 7% of the wheat crop was destroyed by wheat streak mosaic virus. The virus was spread by mites called Aceria tulipae. [39]

In 1970, the Russian plant virologist Joseph Atabekov discovered that many plant viruses only infect a single species of host plant. [37] The International Committee on Taxonomy of Viruses now recognises over 900 plant viruses. [40]

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, [41] and, in 1913, E Steinhardt, C Israeli, and RA Lambert used this method to grow vaccinia virus in fragments of guinea pig corneal tissue. [42] In 1928, HB and MC Maitland grew vaccinia virus in suspensions of minced hens' kidneys. [43] Their method was not widely adopted until the 1950s, when poliovirus was grown on a large scale for vaccine production. [44] In 1941–42, George Hirst (1909–94) developed assays based on haemagglutination to quantify a wide range of viruses as well as virus-specific antibodies in serum. [45] [46]

Influenza Edit

Although the influenza virus that caused the 1918–1919 influenza pandemic was not discovered until the 1930s, the descriptions of the disease and subsequent research has proved it was to blame. [47] The pandemic killed 40–50 million people in less than a year, [48] but the proof that it was caused by a virus was not obtained until 1933. [49] Haemophilus influenzae is an opportunistic bacterium which commonly follows influenza infections this led the eminent German bacteriologist Richard Pfeiffer (1858–1945) to incorrectly conclude that this bacterium was the cause of influenza. [50] A major breakthrough came in 1931, when the American pathologist Ernest William Goodpasture grew influenza and several other viruses in fertilised chickens' eggs. [51] Hirst identified an enzymic activity associated with the virus particle, later characterised as the neuraminidase, the first demonstration that viruses could contain enzymes. Frank Macfarlane Burnet showed in the early 1950s that the virus recombines at high frequencies, and Hirst later deduced that it has a segmented genome. [52]

Poliomyelitis Edit

In 1949, John F. Enders (1897–1985) Thomas Weller (1915–2008), and Frederick Robbins (1916–2003) grew polio virus for the first time in cultured human embryo cells, the first virus to be grown without using solid animal tissue or eggs. Infections by poliovirus most often cause the mildest of symptoms. This was not known until the virus was isolated in cultured cells and many people were shown to have had mild infections that did not lead to poliomyelitis. But, unlike other viral infections, the incidence of polio – the rarer severe form of the infection – increased in the 20th century and reached a peak around 1952. The invention of a cell culture system for growing the virus enabled Jonas Salk (1914–1995) to make an effective polio vaccine. [53]

Epstein–Barr virus Edit

Denis Parsons Burkitt (1911–1993) was born in Enniskillen, County Fermanagh, Ireland. He was the first to describe a type of cancer that now bears his name Burkitt's lymphoma. This type of cancer was endemic in equatorial Africa and was the commonest malignancy of children in the early 1960s. [54] In an attempt to find a cause for the cancer, Burkitt sent cells from the tumour to Anthony Epstein (b. 1921) a British virologist, who along with Yvonne Barr and Bert Achong (1928–1996), and after many failures, discovered viruses that resembled herpes virus in the fluid that surrounded the cells. The virus was later shown to be a previously unrecognised herpes virus, which is now called Epstein–Barr virus. [55] Surprisingly, Epstein–Barr virus is a very common but relatively mild infection of Europeans. Why it can cause such a devastating illness in Africans is not fully understood, but reduced immunity to virus caused by malaria might be to blame. [56] Epstein–Barr virus is important in the history of viruses for being the first virus shown to cause cancer in humans. [57]

Late 20th and early 21st 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. [58] [59] In 1946, bovine virus diarrhea was discovered, [60] which is still possibly the most common pathogen of cattle throughout the world [61] and in 1957, equine arterivirus was discovered. [62] In the 1950s, improvements in virus isolation and detection methods resulted in the discovery of several important human viruses including varicella zoster virus, [63] the paramyxoviruses, [64] – which include measles virus, [65] and respiratory syncytial virus [64] – and the rhinoviruses that cause the common cold. [66] In the 1960s more viruses were discovered. In 1963, the hepatitis B virus was discovered by Baruch Blumberg (b. 1925). [67] 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). [68] This was important to the development of antiviral drugs – a key turning-point in the history of viral infections. [69] In 1983, Luc Montagnier (b. 1932) and his team at the Pasteur Institute in France first isolated the retrovirus now called HIV. [70] In 1989 Michael Houghton's team at Chiron Corporation discovered hepatitis C. [71] 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 [72] and nipah virus [73] have emerged. Despite scientists' achievements over the past one hundred years, viruses continue to pose new threats and challenges. [74]


Renato Dulbecco

Oncogenic viruses, able to elicit tumour formation in animals, have been on the scientific scene for many years. After the early discovery of Ellerman and Bang at the beginning of this century, Peyton Rous opened up the field in its second decade and in prophetic words gave a good hint of things to come. However, these discoveries were soon forgotten and only after a long eclipse was interest in oncogenic viruses revived in the fifties. My involvement in this field began at that time when Rubin and Temin worked in my laboratory with the Rous Sarcoma Virus. When in 1958 polyoma virus, a new oncogenic virus with different properties, was isolated, I jumped at the new opportunity and started working with it. Within a short time polyoma virus became the main interest of my laboratory, to be joined, a few years later by SV40, another papovavirus. It became clear fairly soon that the molecular biology of these viruses could be worked out, and I set out to find the molecular basis of cancer induction. The results that I and a number of brilliant young collaborators have obtained during the following fifteen years have brought us close to that goal. I will review the most interesting steps of our work and will then ask some questions concerning the nature of cancer and about perspectives for prevention and treatment. I stress the relevance of my work for cancer research because I believe that science must be useful to man.

Integration: The provirus
Let me start with a brief review of our work in the molecular events in transformation. The first results, crucial for future developments, showed that polyoma virus could be assayed in certain cell cultures (1), which we call permissive, and could induce a cancer-like state in other cultures (2, 3) in which the virus does not grow, which we call non-permissive. The induction of the cancer-like state in vitro was called transformation. We were able to show that the virus contains DNA (4), and within a few years we gave the first evidence of its cyclic, or circular, shape (5), which is important for two critical biological events: DNA replication and integration. In integration, which we discovered a few years later with SV40 (6), the viral DNA becomes a provirus, i.e. it establishes permanent, covalent bonds with the cellular DNA. The cyclic configuration explains how a complete molecule of the SV40 DNA can be integrated without losses.

Integration is one of the key events in virus induced cell transformation. It explained the persistence of the transformed state in the cell clone deriving from a transformed cell, since the provirus replicates with the cellular DNA. It also permitted us to resolve one of the main questions about the role of viruses in transformation. It was known at the time that papova viruses leave their footprints in the cells of the cancers they induce and those they transform in vitro, in the form of characteristic antigens. However, it was not known whether the antigens were expressed by viral genes or by derepressed cellular genes. Hence, it was uncertain whether cells were transformed by the expression of viral genes persisting in the cells or alternatively if the virus altered the cells by a hit-and-run mechanism, changing the expression of cellular genes and then leaving. The demonstration that viral DNA is integrated in the cells in conjunction with the finding that the provirus is transcribed into messenger RNA (7) hundreds of generations after the establishment of a transformed clone, made the hit-and-run hypothesis unlikely and supported a continuing role of viral gene functions in determining transformation. This possibility was later supported by observations with abortively transformed cells, which behave as transformed only for several generations after infection, but then return to normality (8). When they are back to normal these cells no longer contain the viral DNA (9).

The viral genes that remain unexpressed in the transformed cells, such as those for capsid protein in SV40-transformed cells, were also interesting, although in a different way. In fact their expression could be renewed in hetero-karyons formed by fusing transformed cells with permissive cells (10, 11), a result that gave the first evidence that the viral functions are under the control of cellular functions. The provirus thus became a tool for studying regulation of DNA transcription in animal cells. Subsequently, the presence of giant RNAs containing viral sequences in the nucleus of transformed or lytically infected cells (12) raised the question of the initiation and termination signals for transcription in animal cells, as well as the question of processing of nuclear RNA precursors of messenger RNA, questions that are still largely unresolved.

Viral functions in transformation
Efforts were in the meantime directed at identifying the viral genes transcribed in the transformed cells. It was established that in lytic infection with SV40 the whole viral DNA is transcribed in two nearly equal parts, one early, before the inception of replication of the viral DNA, the other late after DNA replication has begun and that the early RNA is also present in transformed cells (7). Subsequently, the early and the late messengers were found to be transcribed from different DNA strands (13), an observation that facilitated the further characterization of the viral transcripts. Later work in other laboratories using specific fragments produced by restriction endonucleases confirmed and refined these findings and the results were extended to adenoviruses by showing that a segment of the early part of that DNA is always present and transcribed in transformed cells (14, 15).

These facts suggested that some early viral function is essential for maintaining the transformed state but they could also be interpreted differently: for instance, transformation might be caused by the mere presence of the viral DNA in the cellular DNA, the persistent viral functions being perhaps required for establishing and maintaining integration.

Attempts were made to solve the dilemma by isolating temperature sensitive mutants affecting either initiation or maintenance of transformation. Many transformation mutants were found, all clustered in a segment of the early region of the viral DNA, designated as the A gene, but they were all initiation mutants (16, 17, 18). These mutations prevent the onset of transformation at high but not at low temperature, and cells transformed at low temperature remain transformed at high temperature. It was not possible to find clear cut maintenance mutants, i.e. mutations capable of causing a complete reversion of the phenotype when cells transformed at low temperature were shifted to high temperature: however, careful observation later showed that the initiation mutants are also partial maintenance mutants, since the cells they transform undergo a partial reversion of the phenotype at high temperature (19, 20, 21). This result shows that the viral genes play a continuing role in transformation however, the failure to obtain complete maintenance mutants suggests that the relation between viral gene expression and cell phenotype is complex.

Search for the viral transforming protein
Further progress in this subject has been achieved by studying the proteins specified by the early region of the viral DNA. This work has centred around the so-called T antigen (22) present in the nucleus of cells infected or transformed by SV40 and whose synthesis and properties are affected by mutations of the A gene (23, 24, 25). In non-permissive transformed cells the antigen is a protein of molecular weight of about 94,000 daltons (26), which binds firmly to double-stranded DNA, but without much specificity (27, 28, 29). That the T antigen is specified by the viral DNA is strongly suggested by its in vitro synthesis using a wheat germ extract primed with various messengers (30), especially since the size of the product depends on the nature of the messenger. Thus, when the messenger was viral RNA made in vitro by transcribing SV40 DNA with E. coli RNA polymerase, an antigenic protein of about 62,000 daltons was synthesized but when mRNA extracted from infected cells was used the protein synthesized was, like the T antigen of transformed cells, of about 94,000 daltons. The discrepancy of the two molecular weights makes it very unlikely that the T antigen is a cellular protein modified by a viral function, because two different proteins would have to be modified in the same extract depending on the messenger used. In contrast, the synthesis of a shorter polypeptide chain with the artificial messenger may be justified by the absence of accessory signals, such as cap, poly A, and possibly other modifications. Further definition of these findings awaits peptide maps of the various products.

Since the early, transforming part of the SV40 genome can specify proteins of a molecular weight of about 100,000 daltons altogether, the T antigen is likely to be its sole product and, therefore, to be the transforming protein. However, the same protein must also initiate viral DNA replication, which cannot initiate at high temperature in cells infected by mutants of the A gene. The different functions in transformation and lytic infections could be performed by different domains of the same protein, or could result from modifications (such as phosphorylation and glycosylation) or from processing. Processing of SV40 T antigen seems to occur in lytically infected cells which contain a smaller T antigen of about 84,000 daltons this smaller size contrasts with the regular size (94,000 daltons) of the antigen specified in vitro by mRNA extracted from the same cells (26). Whether the two forms of the antigen have different roles in transformation and DNA replication still remains to be established.

Since the transforming protein should control both initiation and maintenance of transformation the partial reversion of the phenotype of cells transformed by A mutants when shifted to high temperature may be explained by a decreased requirement for the transforming protein once transformation has taken place, which in turn could result from a positive feedback stabilizing the transformed state. For instance, unstable protein monomers specified by the mutated gene might form self-stabilizing oligomers (31), or the transforming protein might generate changes that tend to favour the transformed state. An example of the latter model is the beta galactosidase induction in E. coli which is maintained by inducer concentrations much smaller than that required for initiating induction, because inducer is pumped into the cells by the induced permease (32). I wonder whether a certain degree of self-stabilization of the state of gene expression is a general property of animal cells, which has developed for maintaining differentiation.

Cellular events in transformation
I now wish to turn to cellular events participating in transformation, which will be the main problem after the remaining questions on the role of the virus have been answered. Among the cellular events are functional changes and mutations. Some functional changes, which affect many cellular properties, are associated with the shift of resting cells to growing state after infection with polyoma virus or SV40 (33, 34) other changes observed in transformed and in cancer cells in general consist of the re-expression of cellular genes normally expressed in a preceding state of differentiation, in foetal life (35). These functional changes might be caused by the binding of transforming proteins to DNA if so they may be mediated by an alteration of transcription of the cellular DNA. However, we do not know whether the transcription pattern changes because experiments based on competition hybridization have given ambiguous results. Perhaps the methodology is not good enough. Cloning of cellular DNA fragments in phages or plasmids may afford the necessary probes for carrying out significant experiments.

In order to understand further how the virus deregulates cellular growth we would need a detailed knowledge of the mechanisms of growth regulation in animal cells, which is now lacking. However, certain useful ideas about growth regulation are now available and can be used to draw inferences on the action of the virus. Thus, it seems clear that with a given cell type growth regulation involves a complex chain of events, beginning with extracellular regulators of many kinds, probably interacting with the cell plasma membrane. Cytoplasmic mediators then appear to transmit regulatory signals from the plasma membrane to the nucleus, where they perhaps control DNA-binding proteins similar to the transforming protein of papova viruses. The complexity of growth regulation increases markedly when different cell types are considered, since they seem to recognize different sets of extracellular regulators and may have different mediators and DNA binding proteins.

Proceeding from this general picture it would be tempting to propose that the viral transforming protein replaces one of the normal nuclear regulatory proteins of the cell, and being unaffected by the mediators that control the normal protein, keeps growth related transcription going, bypassing the signals of the plasma membrane. If so, however, the transformed state should be dominant over the normal state in cell hybrids, whereas the contrary is usually true (36). On the other hand, the dominance of the normal state could be explained if the transformed cells had a changed surface, unable to respond to regulatory signals. Such a change could result from the re-expression of foetal functions to make the transformed cells anachronistic, i. e. belonging to a stage of differentiation inappropriate to that of the organism which contains them. The cells with an anachronistic surface being insensitive to the growth regulators present in the adult organisms, which operate on adult cells, would grow without control. A striking support of the role of cell anachronism in cancer has been obtained with teratoma, a tumour originating when cells from an early embryo are transplanted to an adult environment. When, after many transplants cells of this tumour are introduced back into a blastocyst, i.e. an early embryo, they return to normality (37, 38), presumably because the internal growth control of the cells becomes again matched by the environmental regulators of the recipient embryo. In this model a hybrid cell formed by fusing a transformed and a normal cell may be untransformed, if the normal partner contributes normal surface components which respond to the normal extracellular regulators. For this result to be possible, anachronistic transcription should not be initiated after cell fusion on the DNA deriving from the normal parent. The virological studies suggest that this may well be the case, since the initiation of transformation seems to require much more transforming protein than its maintenance.

It would be important to recognize the developmental period during which the anachronistic genes of transformed or cancer cells are normally expressed, not only for understanding but possibly also for controlling cancer. In fact, if the growth regulators specific for the periods expressed in cancer cells could be identified they could be used for halting the growth of the cancer cells.

Role of cellular mutations
I will now consider the other cellular events important in viral transformation, i. e. cellular mutations. Several results suggest that cellular mutations may be needed for obtaining the full state of transformation with papova viruses. Thus, after infection primary cultures generate clones with various degree of transformation, some of which appear to undergo full transformation in steps (39) which may correspond to the occurrence of cellular mutations. Cells that achieve full transformation immediately, as are common with permanent lines, may have already undergone similar mutations before infection. Some cellular mutations occurring in transformed cells may even be virus-induced, because in the early stages of transformation by papova viruses cells of primary cultures have frequent chromatid breaks (39). Conversely, cells fully transformed by SV40 can revert to a relatively normal phenotype although they still contain normal viral DNA and T antigen (40, 41). It is conceivable that these mutations are reversions of mutations of the former kind, which enhance the transformed state of the cells. Stepwise transformation may not only occur with viruses. Thus, I have observed it in primary cultures exposed to a chemical carcinogen. In this experiment fully transformed cells evolved from the normal cells, which have limited life, generating first cells with unlimited life but unable to form colonies in agar, then cells with progressively increasing colony forming efficiency in agar, to finally reach 100% efficiency.

All these observations show the important role of cellular mutations in cell transformation induced by different agents. This conclusion is reinforced and generalised by additional findings, such as 1) the experimental enhancement of the transforming activity of viruses by mutagenic agents (42), (2 by the elevated cancer frequency in some genetic diseases, and 3) by the evidence that most carcinogens are promutagens, i.e. generate mutagenic substances when acted upon by normal metabolism (43). Most of the carcinogens themselves must be activated by metabolism in a similar way in order to induce cancer.

Prospects for cancer prevention
I will now turn to some general deductions concerning the etiology and possible prevention of human cancer, which derive from the various points I have discussed so far. One deduction, deriving from the persistence of the viral DNA in the cells is that we can test whether a given DNA virus is a possible agent of human cancer by looking for its DNA in the cancer cells. I think that much more extensive surveys than those carried out so far are warranted, but they should have a sensitivity sufficient to detect fragments of viral DNA of about one million daltons, which is within the reach of modern technology, even with the most difficult viruses. A positive finding would be significant because DNA viruses do not appear to exist in widespread endogenous forms.

Another deduction is that somatic mutations are one of the fundamental ingredients of cancer although they appear to require the occurrence of several other events not yet understood. The role of mutations in turn suggest that the incidence of cancer in man could be reduced by identifying as many promutagens as possible, and by eliminating them from the environment. One important feature of this approach to cancer prevention is that it can be started now, since these substances can be identified with simple bacterial tests suitable for mass screening (44). The feasibility of prevention is shown by the fact that the promutagens already identified in a preliminary screening, such as tobacco or some hair dyes, are inessential for human life (45, 46).

However, it is practically difficult to achieve a substantial reduction of the use of these substances, as shown by the example of tobacco. According to epidemiological evidence tobacco smoke is the agent of lung cancer in man, which in Britain is responsible for one in eight of all male deaths (47). Yet only mild sanctions have been imposed on tobacco products, such as a vague health warning on cigarette packets, which sounds rather like an official endorsement. Any limitation on the use of tobacco is left to the individual, although it is clear that the individual cannot easily exercise voluntary restraint in the face of very effective advertisements, especially as he does not usually appreciate the danger of a cumulative action over a long period of time.

The lax attitude of governments towards tobacco probably also derives from the difficulty of appreciating epidemiological evidence, especially since this evidence is contradicted from time to time by single-minded individuals who use incomplete or even erroneous analyses of the data, and whose views are magnified out of all proportion by the media. However, the recent recognition that tobacco smoke contains promutagens contributes direct experimental evidence on the dangers of tobacco smoke, on which there cannot be any equivocation. I, therefore, call on governments to act towards severely discouraging tobacco consumption and to act now because it will be at least thirty years before their action has its full effect.

Although tobacco smoke is a striking example of an environmental carcinogen, many others are known and probably many more remain to be identified. Identification by conventional tests is difficult because they are costly and laborious but they can now be replaced by the bacterial tests for promutagens. Since the tests are easy and inexpensive it should be possible to investigate many normal constituents of the environment, and every new compound before it is offered to the public. The feasibility of such a programme is borne out by the finding that most of the commonly available substances are not promutagens (45, 46). Given the strong correlation between mutagenicity and carcinogenicity (43), any promutagen is suspect and, if all possible, should be withdrawn.

In fact, this is precisely the attitude that scientists have taken for them-selves concerning the experiments in genetic engineering, which carry the theoretical possibility of creating new virus-like molecules, endowed with carcinogenic activity. Although the danger is only hypothetical, experiments which might be very useful for science and society have been postponed until they can be carried out under the strictest safeguards (48). Governments have accepted this position and are eager to impose severe restrictions on the performance of these experiments. While I fully approve of their concern, I cannot help noticing that they follow a double standard if there is any doubt – you must discourage experiments, but if there is any doubt – you cannot discourage cigarettes.

Biologists and society
This discussion about cancer prevention is a development of the experimental results obtained in the field of oncogenic viruses, but it is also strongly influenced by the new social conscience of many scientists. Historically, science and society have gone separate ways, although society has provided the funds for science to grow and in return science has given society all the material things it enjoys. In recent years, however, the separation between science and society has become excessive, and the consequences are felt especially by biologists. Thus, while we spend our life asking questions about the nature of cancer and ways to prevent or cure it, society merrily produces oncogenic substances and permeates the environment with them. Society does not seem prepared to accept the sacrifices required for an effective prevention of cancer. The situation is clearly unacceptable, and we biologists would like to see it corrected. We have ourselves begun to put our house in order, by banning some experiments that may contain a risk for mankind. We would like to see society take a similar attitude, abandoning selfish practices that are dangerous for society itself. We would also like to see a new co-operation of science and society for the benefit of all mankind and hope that the dominant forces in society will recognize that this is a necessity.

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Copyright © The Nobel Foundation 1975

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Nobel Prizes 2020

Twelve laureates were awarded a Nobel Prize in 2020, for achievements that have conferred the greatest benefit to humankind.

Their work and discoveries range from the formation of black holes and genetic scissors to efforts to combat hunger and develop new auction formats.


Retroviruses

Members of one family of RNA viruses, the retroviruses, cause cancer in a variety of animal species, including humans. One human retrovirus, human T-cell lymphotropic virus type I (HTLV-I), is the causative agent of adult T-cell leukemia, which is common in parts of Japan, the Caribbean, and Africa. Transformation of T lymphocytes by HTLV-I results from expression of the viral gene tax, which encodes a regulatory protein affecting expression of several cellular growth control genes. AIDS is caused by another retrovirus, HIV. In contrast to HTLV-I, HIV does not cause cancer by directly converting a normal cell into a tumor cell. However, AIDS patients suffer a high incidence of some malignancies, particularly lymphomas and Kaposi's sarcoma. These cancers, which are also common among other immunosuppressed individuals, apparently develop as a secondary consequence of immunosuppression in AIDS patients.

Different retroviruses differ substantially in their oncogenic potential. Most retroviruses contain only three genes (gag, pol, and env) that are required for virus replication but play no role in cell transformation (Figure 15.17). Retroviruses of this type induce tumors only rarely, if at all, as a consequence of mutations resulting from the integration of proviral DNA within or adjacent to cellular genes.

Figure 15.17

A typical retrovirus genome. The DNA provirus, integrated into cellular DNA, is transcribed to yield genome-length RNA. This primary transcript serves as the genomic RNA for progeny virus particles, and as mRNA for the gag and pol genes. In addition, (more. )

Other retroviruses, however, contain specific genes responsible for induction of cell transformation and are potent carcinogens. The prototype of these highly oncogenic retroviruses is Rous sarcoma virus (RSV), first isolated from a chicken sarcoma by Peyton Rous in 1911. More than 50 years later, studies of RSV led to identification of the first viral oncogene, which has provided a model for understanding many aspects of tumor development at the molecular level.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.


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