Four Stages in the History of Interferon Research

Abstract

A period of 30 years, from the discovery of interferon to the present, may just be an instant in the history of science and medicine, but that seems to be long enough for interferon research to mold its own highly interesting history. I am glad to join in this homage to Jean Lindenmann by presenting my view of that history. But let me begin with some personal recollections. FOREIGN RNA AND INVERSE INTERFERENCEMy interest in interferon was first aroused by Alick Isaacs' idea, published in 1963, that animal cells respond to foreign nucleic acid by producing interferon." 21 I was trained in physical chemistry but turned to molecular biology under the influence of Itaru Watanabe, one of the founders of that discipline in postwar Japan. I had been for some time interested in the structure and function of RNA. The early 1960s were the time when the genetic code was finally being deciphered, and various aspects of Francis Crick's Central Dogma were receiving ample experimental support. I was busy working on all sorts of RNA, from transfer RNA to virus RNA and "rapidly labeled RNA" of cultured animal cells.'31 One thing I was particularly interested in was whether viral RNAs could replicate in any kind of cell. It had earlier been shown that replication of poliovirus can proceed in cells that are "insusceptible" to intact virus (due to lack of the virus receptor), if the cells are infected with naked, infectious RNA. I wanted to see how far this could be generalized, and tried some experiments such as infection of Escherichia coli spheroplasts with infectious picornavirus RNA, and that of animal cells with infectious bacteriophage MS2 RNA. The results were negative. But my colleague T. Fukada did find that chick embryo cell cultures treated with the phage RNA (single-stranded) became resistant to several viruses.'4' As we had been fascinated by Isaacs' hypothesis of foreign nucleic acid, we tried various RNAs. Some of the RNAs we tested were effective, but many were not, and we could not identify the structural or other features of RNA responsible for the interference induction.'51 Neither was support obtained for Isaacs' hypothesis. We even examined some double-stranded RNAs that were then available to us, namely, rice dwarf virus RNA and poly(I):poly(C). Most of the time, they were toxic to the cells, and we did not pursue them with enthusiasm (we used microgram quantities as with single-stranded RNA, and did not realize that they were too large), until one day in 1967 we were stunned by a beautiful paper from