Isaacs and Lindenmann Discover Interferons

Date 1957

While seeking to understand why humans catch only one viral disease at a time, Alick Isaacs and Jean Lindenmann discovered interferons, the proteins produced by body cells to fight viral diseases and potential tools to fight cancer.

Locale Mill Hill, England

Key Figures

• Alick Isaacs (1921-1967), Scottish physician and microbiologist who discovered interferons
• Jean Lindenmann (b. 1924), Swiss researcher who helped discover interferons
• Macfarlane Burnet (1899-1985), Australian microbiologist

Summary of Event

Over half of the communicable diseases that inconvenience, harm, and even kill humans are caused by viruses that contain ribonucleic acid (RNA) as their hereditary material. This RNA generates the ability of these “RNA viruses” to cause human disease, once a virus infects a human cell. The diseases caused by RNA viruses include the common cold, the measles, influenza, polio, and even some types of cancer. Viral diseases are unaffected by antibiotics, the therapeutic miracle drugs that cure infectious bacterial diseases. The only common, chemotherapeutic defense against viral diseases that the body cannot fight off (for example, crippling polio) is their prevention by the use of vaccines.

It has been known for many years that people do not catch more than one viral disease at a time. This is thought to be caused by the biological action of proteins, called interferons, secreted by virus-infected cells. There are three kinds of interferons: leukocytic, fibroepithelial, and immune types. The fibroepithelial and leukocytic interferons are believed to be most important in protection against viral infection. The interferon type produced in response to a viral invasion, however, depends on the kind of body cell that is infected and on the infecting virus involved.

Interferons are present in both plants and animals. In all the organisms that contain interferons, they are believed now to act as the primary cellular defense against viruses. Not only do interferons destroy the original infecting viruses, but also they protect organisms from many other viruses after a specific virus attack. The discovery of interferons is credited to Alick Isaacs and Jean Lindenmann. Isaacs, a physician-microbiologist, received his medical training at Glasgow University; however, he preferred basic research to clinical medicine. Therefore, he entered into graduate study of bacteriology, working with eminent microbiologists such as Macfarlane Burnet. He began study of viral influenzas (now known to be caused by an RNA virus). Understanding influenza remained Isaacs’s primary research goal throughout his career.

Isaacs’s discovery of interferon arose from his examination of the so-called viral interference phenomenon. That is, the observation that any RNA virus usually can prevent the growth, in a cell, of other RNA viruses added to it. Isaacs’s first efforts—carried out in Australia—showed that the interference caused by influenza viruses had nothing to do with the penetration of cells by the viruses. Rather, it appeared to be caused by an event that occurred in the interior of the infected cell. In 1951, Isaacs returned to England to work in the National Institute for Medical Research at Mill Hill. He continued his study of viral interference and of influenza viruses. His collaboration with Lindenmann—a visiting Swiss scientist—produced the crucial experiments (in 1957) that led to their being credited with the discovery of the interferons.

Two very important initial discoveries that Isaacs and Lindenmann made with in vitro experiments: The interfering agent was present in the culture fluid around the tissue samples being studied, and the infected tissues were stimulated to produce the interfering agent. They named the uncharacterized interfering agent interferon. Subsequent study demonstrated that this interferon was a protein or a substance that required a protein for its action.

The discovery of interferon identified what appeared to be a new, important mechanism for defense against viral infection. It seemed likely that interferon would have exceptional therapeutic value because it worked against many different viruses, not only against the one that caused its production. In 1961, Isaacs was appointed to head the virus research division at Mill Hill. The crusade to understand interferon action was under way around the world. Isaacs participated also in the World Health Organization’s efforts to better understand influenza.

Soon, however, the molecular basis for interferon action was identified. It was found that entry of an RNA virus (actually its RNA core) into a cell causes the cell to produce interferon, which is then secreted from the cell, or released from the cell if the RNA virus infection kills it. The interferon molecules released in these ways come into contact next with uninfected cells. They interact with these cells and confer on them a great resistance to the original, infecting RNA virus and to a large number of other RNA viruses that would otherwise be infectious.

Interferons prevent viruses from killing protected cells by stopping the usual sequence of events that occurs when a virus infects a cell. That is, the virus interacts with the cell, penetrates its cell membrane, and releases its RNA core into the cell. The RNA core converts the cell to a virus factory that makes the viral RNA and the viral proteins that will become new viruses (viral progeny); these viral components are assembled and become hundreds of viral progeny; the viral progeny destroy the infected cell, enter other nearby cells, and start the process over again; and the steps are repeated over and over again.

Interferons act by stopping the synthesis of both viral proteins and viral RNA. This results from the fact that interferons cause cells to produce two proteins.

Significance

Many years have passed since the work of Isaacs, Lindenmann, and their associates spotlighted the interferons. Examination of these potentially important chemicals has progressed slowly because of their scarcity and the difficulty involved in the manufacture of pure interferons. Nevertheless, the consequences of the discovery of the interferons and existing studies of their biological properties have been exciting in several ways.

For example, it is widely believed now that interferons are the cell’s first line of defense against viral infection and that production of the appropriate interferon will lead to the destruction of most infectious RNA viruses. Furthermore, a causal relationship between interferons and natural recovery from viral infections has developed from numerous experiments.

A second exciting aspect of interferon action relates to cancer therapy. Interferon use evolved from the observation that many types of cancer cell tissue cultures are killed by the addition of interferons. One reported example of therapeutic use of interferon against cancer is treatment of osteogenic sarcoma, a bone cancer that often attacks teenagers. This cancer which usually kills 85 percent of those afflicted, is now treated successfully via interferons. Furthermore, reports of other valuable interferon-based cancer therapy fill the literature of cancer research.

Bibliography

Andrewes, Christopher H. “Alick Isaacs.” Dictionary of National Biography. Vol. 2. New York: Oxford University Press, 1982. Brief biographical essay on Isaacs discusses his life and work, including events leading to his discovery of interferon with Lindenmann.

Baron, Samuel. “Interferon.” McGraw-Hill Encyclopedia of Science and Technology. 20 vols. 9th ed. New York: McGraw-Hill, 2002. Exposition of interferons presents a description of interferon production, interferon types, the mechanism of their action, their properties, and their possible role in cancer therapy. Includes references to animal viruses, cancer, virus interference, and study of interferons.

Burke, Derek C. “The Status of Interferon.” Scientific American, April, 1971, 42-50. Describes the protein nature of interferon and explains some aspects of its purification, action mechanism, and attempted use in chemotherapy. Also points out some tribulations in proving its chemotherapeutic efficacy and its promise as a chemotherapeutic agent against serious viral diseases.

Edelhart, Mike, with Jean Lindenmann. Interferon: The New Hope for Cancer. Reading, Mass.: Addison-Wesley, 1981. Explains how interferons work, describes the discovery of interferon, and traces the development of interferon research from basics to modern genetic engineering. A good introduction to interferon.

Pieters, Toine. Interferon: The Science and Selling of a Miracle Drug. New York: Routledge, 2005. Presents a history of interferon, its manufacture and sale, and its healing properties.

Stewart, William E., II, et al., eds. Interferons and Their Actions. Cleveland, Ohio: CRC Press, 1977. This highly technical text is of most use to readers who wish detailed information. It contains nine chapters that deal with topics including the mechanism of interferon induction, regulation of the process, the purification of interferons, the genetics of human interferons, possible mechanisms of its antiviral activity, and interferon chemotherapy. Hundreds of references are cited.

Zubay, Geoffrey. Biochemistry. 4th ed. Dubuque, Iowa: William C. Brown, 1998. Brief description of interferons and their actions that identifies the three types of interferons, differentiates between them, and describes the mechanism by which they operate. Includes a brief diagrammatic representation of interferon action.