Peyton Rous’s discovery that a liver sarcoma (connective tissue cancer) in chickens is caused by a virus revolutionized the understanding of cancer genetics.
During the last half of the nineteenth century, tremendous progress was made in a new area of biology called microbiology,
The microbial world consists of many species, ranging from protozoa to fungi to bacteria. The nineteenth century work of Matthias Jakob Schleiden
Peyton Rous.
In 1892, the Russian microbiologist Dmitri Ivanowski was attempting to discover the cause of tobacco mosaic disease, an infection that was decimating Russian tobacco crops. Filtering infected tobacco juice failed to remove the agent responsible for the disease, thus something smaller than a bacterium had to be the culprit. Using filters with smaller and smaller pores, Ivanowski demonstrated that the causative agent was approximately one hundred to one thousand times smaller than bacteria. This new organism, called a virus, was approximately 0.001 to 0.01 micrometer long and had a unique pattern of infection. The Dutch botanist Martinus W. Beijerinck
In the early twentieth century, viruses were shown to be noncellular in structure, consisting only of nucleic acid—that is, deoxyribonucleic acid (DNA) or ribonucleic acid (RNA)—wrapped within a protective protein covering. Viruses are immobile and inactive outside cells. They can function only within host cells, and then only to reproduce and destroy the host cells. They are obligate intracellular parasites, always invading cells, raping cellular resources, reproducing, and destroying. Because of the noncellular structure and unusual nature of viruses, considerable debate exists regarding their classification as a life-form.
Once a virus is carried by air or fluid to the cells of a given host species, it may be only by chance that it physically contacts a cell. After such contact is made, a rapid series of chemical reactions between the virus protein covering and the cell membrane triggers the injection of the viral DNA or RNA into the cell. Once it is inside the host cell, the viral nucleic acid can follow two possible infection routes, depending on cellular conditions and certain enzymes encoded by the viral nucleic acid:
In 1909, Peyton Rous began research in pathology at the Rockefeller Institute for Medical Research (now Rockefeller University) in New York City. Rous was interested in the physiology of cancer within mammals and birds. He discovered a type of connective tissue cancer in chickens, subsequently named Rous sarcoma, that causes gross hypertrophy (enlargement) of certain organs, particularly the liver and gallbladder, and is eventually fatal. In his experiments, Rous grafted sarcoma tumor cells from diseased hens to healthy hens, and the healthy hens contracted the disease. He then cultivated hen tumor cells, extracted a fluid not containing cells, and injected this fluid into healthy hens. Again, the healthy hens contracted the disease.
By 1910, Rous concluded that his results pointed toward one possible explanation: Some noncellular component of the tumor extract was capable of producing cancer in healthy hens. The active agent was not bacterial, protozoan, or fungal, because the tumor extract contained no cells. The most plausible explanation was a virus. Further filtration and infection experiments yielded identical results. Rous hypothesized that a Rous sarcoma virus caused this chicken sarcoma. Nevertheless, his work was derided by his peers, who unsuccessfully repeated his experiments with other species. The failure of many to accept Rous’s conclusion reflected a considerable lack of understanding of both viruses and cancer by the medical and scientific community of that time. Despite the negative reactions, Rous continued his studies of liver and gallbladder physiology.
With greater understanding of viruses during subsequent decades of the twentieth century, Rous’s viral theory of cancer began to be recognized. From his studies of Rous sarcoma virus, his theory maintained that some cancers could be caused by viruses. The discovery of more tumor-causing, or oncogenic, viruses during the 1950’s resulted in Rous’s receiving the 1966 Nobel Prize in Physiology or Medicine, which he shared with Charles Brenton Huggins.
Among the oncogenic viruses identified since Rous’s initial discovery are the RNA tumor viruses feline leukemia virus (cat leukemia), T-cell lymphotropic virus (human leukemia), and mouse mammary tumor virus. The Rous sarcoma virus also was later shown to be an RNA retrovirus whose nucleic acid is RNA. DNA oncogenic viruses include hepatitis B (serum hepatitis and liver cancer), papilloma virus (warts), the Epstein-Barr virus (mononucleosis and Burkitt’s lymphoma), and herpes simplex virus II (genital herpes and cervical cancer).
Oncogenic viruses are capable of cellular transformation, converting normal cells to abnormal growth patterns. The abnormal cell growth may proceed with rapid cellular divisions, gain or loss of chromosomes, and unusual production of certain proteins. If the tumor begins to invade neighboring healthy tissues and to enter the bloodstream for transport to other body regions (metastasis), then the tumor has become a cancer with life-threatening potential.
Oncogenic viruses are transmitted in the same ways other viruses are, principally by air, through liquid, or by direct contact, or especially through the transfer of bodily fluids. Once an oncogenic virus contacts a target cell, it proceeds either into the lytic or the lysogenic cycle. If the virus follows a lytic pathway, it releases proteins capable of cellular transformation, thus causing the host cell to become cancerous and to multiply out of control. As the tumor cell multiplies, it produces more viruses that bud off from the tumor cell membrane to infect neighboring cells. If the virus follows a lysogenic pathway, it may be dormant within the host cell DNA for years before emerging, entering the lytic cycle, and transforming the cell into a tumor.
Interest in the Rous sarcoma virus resurfaced in the 1960’s with Rous’s Nobel Prize and with the work of two molecular virologists, Howard M. Temin and David Baltimore. Temin discovered that the Rous sarcoma virus can copy a DNA polynucleotide chain from the viral RNA originally injected into the host cell. Soon thereafter, Temin and Baltimore independently discovered the enzyme reverse transcriptase, which RNA retroviruses use to encode DNA from RNA. This discovery overturned the molecular biological view that DNA encodes RNA exclusively. Although Temin’s and Baltimore’s results initially were seriously questioned, mounting evidence led to these two scientists’ receiving the Nobel Prize in Physiology or Medicine in 1975.
The discovery that Rous sarcoma is caused by a virus not only helped to reaffirm Ivanowski’s discovery of viruses as pathogens but also revealed that some cancers are infectious, being spread from individual to individual through viruses. Rous’s viral theory of cancer cast a totally new perspective on the disease.
The Rous sarcoma virus was the first of many oncogenic viruses discovered during the twentieth century. Most of these, including the Rous sarcoma, are classified as low-risk oncogenic viruses, whereas others are considered to be of moderate risk. Several of these viruses cause other diseases in addition to cancer. For example, the Epstein-Barr virus
In addition to changing how some forms of cancer are viewed, Rous’s discovery paved the way for a better understanding of the origin of viruses. Viruses most likely evolved from cells, given that viruses are noncellular, they must reproduce inside cells, and they have the same genetic code as living cells. It is possible that more than one billion years ago a small group of genes capable only of reproduction and of manufacturing a protective protein covering escaped from a cell and temporarily existed outside cells in an inactive, dormant state. Viruses could be intercellular messengers whose functions went awry.
In the 1960’s, Temin and Baltimore demonstrated that RNA retroviruses, such as Rous sarcoma virus, could encode DNA from RNA using a special viral enzyme called reverse transcriptase. This phenomenon went against established scientific dogma, which maintained that DNA encodes RNA. The list of such RNA retroviruses includes the notorious human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS) in humans. HIV causes AIDS, but it does not cause cancer; instead, it destroys immune system cells such that an individual’s body is unable to defend itself from secondary infections, such as pneumonia, and spontaneous cancers.
The knowledge that viruses can induce tumors in normal cells has informed research aimed at manipulating viruses as cloning vectors. A molecular biologist can clone a particular gene of interest, package the gene within a virus’s DNA, and then infect a desired target cell with the virus. If the virus DNA enters the lysogenic cycle once it is inside the target cell, then the scientist effectively will have cloned a specific gene into a host cell’s DNA using the virus as a transport mechanism.
In addition, the study of viruses as disease- and cancer-causing agents led to the discovery of even smaller life-forms that also cause disease. The prion, a little-understood mass of protein containing no nucleic acid, has been implicated in a number of mammalian diseases of the central nervous system, including scrapie, kuru, and Creutzfeldt-Jakob disease.
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Bishop, J. Michael. “Oncogenes.” Scientific American 246 (March, 1982): 80-92. Review article by a major oncogenic virus researcher discusses how oncogenic viruses infect cells and initiate cancer. Describes the Rous sarcoma virus, along with the work of Rous, Temin, and Baltimore. Includes superb diagrams and illustrations. -
Cooper, Geoffrey M. Oncogenes. 2d ed. Boston: Jones and Bartlett, 1995. Comprehensive text provides an overview of oncogene research and details advances in the field. Includes glossary and index. -
Lechevalier, Hubert A., and Morris Solotorovsky. Three Centuries of Microbiology. 1965. Reprint. Mineola, N.Y.: Dover, 1974. Outstanding detailed history of microbiological research from the 1600’s to the mid-1960’s, including the many famous experiments of Pasteur, Koch, Ivanowski, and Rous. Chapter 8 describes Rous’s famous experiment and includes quotations from his 1911 paper in the Journal of the American Medical Association. -
Lewin, Benjamin. Genes VI. New York: Oxford University Press, 2005. Textbook of molecular biology for advanced undergraduate and graduate students provides a thorough, detailed survey of the science behind biotechnology. Includes excellent illustrations. -
Raven, Peter H., et al. Biology. 7th ed. New York: McGraw-Hill, 2004. Outstanding introductory biology textbook for undergraduate biology majors. Clearly written and features beautiful photographs and other illustrations. Provides very good description of the lytic and lysogenic cycles, classification of viruses, and tumor-causing viruses. -
Snustad, D. Peter, and Michael J. Simmons. Principles of Genetics. 4th ed. New York: John Wiley & Sons, 2004. Outstanding introductory genetics textbook for undergraduate biology majors provides a comprehensive survey of the field. Clearly written, with numerous diagrams and illustrations. Includes a good discussion of oncogenes. -
Wistreich, George A., and Max D. Lechtman. Microbiology. 5th ed. New York: Macmillan, 1988. Excellent introductory textbook for undergraduate biology students covers every aspect of microbiology in extensive detail, supported by a plethora of charts, diagrams, tables, and photographs. Great book for the serious microbiologist.
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