Interferon - History

History

During research to produce a more efficient vaccine for smallpox, Yasu-ichi Nagano and Yasuhiko Kojima—two Japanese virologists working at the Institute for Infectious Diseases at the University of Tokyo—noticed inhibition of viral growth in an area of rabbit-skin or testis previously inoculated with UV-inactivated virus. They hypothesised that some "viral inhibitory factor" was present in the tissues infected with virus and attempted to isolate and characterize this factor from tissue homogenates. In 1954, these findings were published in a French journal now known as the Journal de la Société de Biologie. After Nagano and Kojima separated the viral inhibitory factor from the viral particles using ultracentrifugation, they confirmed its antiviral activity lasted 1–4 days and did not result from antibody production; their findings were published in 1958. Nagano’s work was never fully appreciated in the scientific community; possibly because it was printed in French, but also because his in vivo system was perhaps too complex to provide clear results in the characterisation and purification of interferon.

Meanwhile, the British virologist Alick Isaacs and the Swiss researcher Jean Lindenmann, at the National Institute for Medical Research in London, noticed an interference effect caused by heat-inactivated influenza virus on the growth of live influenza virus in chicken egg chorioallantoic membrane. They published their results, attaining wide recognition, in 1957; in this paper they coined the term "interferon", and today that specific interfering agent is known as a "Type I interferon". Independently, Monto Ho, in John Ender's lab, made a seminal discovery in 1957 that the RMC virus conferred a species specific anti-viral effect in human amniotic cell cultures. They named this effect the viral inhibitory factor (VIF). Subsequently, Enders and Issacs agreed that the VIF and Interferon belonged to the same class of viral inhibitory factors. The majority of the credit for discovering interferon goes to Isaacs and Lindenmann, with whom there is no record of Nagano ever having made personal contact. It took another fifteen to twenty years, using somatic cell genetics, to show that the interferon action gene and interferon gene reside in different human chromosomes. The purification of human beta interferon did not occur until 1977. Chris Y.H. Tan and his co-workers purified and produced biologically active, radio-labeled human beta interferon by superinducing the interferon gene in fibroblast cells, and they showed its active site contains tyrosine residues. Tan's laboratory isolated sufficient enough amounts of human beta interferon to perform its first amino acid, sugar composition and N-terminal analyses . They showed that human beta interferon was an unusually hydrophobic glycoprotein. This explained a large loss of interferon activity when interferon preparations were transferred from test tube to test tube or from vessel to vessel during purification. The analyses ascertained once and for all, the reality of interferon activity by chemical verification. The purification of human alpha interferon was not reported until 1978. A series of publications from the laboratories of Sidney Pestka and Alan Waldman between 1978 and 1981, describe the purification of the type I interferons IFN-α and IFN-β. By the early 1980s, the genes for these interferons were cloned, allowing for further definitive proof that interferons really were responsible for interfering with viral replication. Gene cloning also confirmed that IFN-α was encoded by, not one gene, but a family of related genes. The type II IFN (IFN-γ) gene was also isolated around this time.

Interferon was scarce and expensive until 1980, when the interferon gene was inserted into bacteria using recombinant DNA technology, allowing mass cultivation and purification from bacterial cultures or derived from yeast (e.g. Reiferon Retard is the first yeast derived interferon-alpha 2a) Interferon can also be derived from recombinant mammalian cells. Before this, in the early 1970s the large scale reproduction of human interferon was pioneered by Kari Cantell. He produced large amounts of human alpha interferon from massive quantities of human white blood cells collected from and by the Finnish Blood Bank. Large amounts of human beta interferon were made by superinducing the beta interferon gene in human fibroblast cells, a procedure Chris Y.H.Tan discovered with Monto Ho. Cantell's and Tan's methods of making large amounts of natural interferons were critical to make purified interferons for their chemical characterisation,for their clinical trials and for the preparations of the scarce amount of interferon messenger RNAs to the clone the human alpha and beta interferon genes. The superinduced human beta interferon messenger RNA was prepared by Tan's lab for Cetus corp. to clone the human beta interferon gene into bacteria and the recombinant interferon was developed as 'betaseron' and approved for the treatment of MS. Superinduction of the human beta interferon gene was also used by Israeli scientists to manufacture human beta interferon, used as a topical anti-herpes agent.