A tribute to Jean Lindenmann, co-discoverer of interferon (1924-2015).

In 1957, the discovery of interferon was reported by Isaacs and Lindenmann in the prestigious journal Proceedings of the Royal Society (1957) [1,2]. This discovery was definitely one of the scientific landmarks in cell biology of the past century. It was the result of an initially unplanned and amazingly creative collaboration with Alick Isaacs that lasted from July 1956 to June 1957 at Mill Hill in London. Jean Lindenmann died in Zürich on January 15, 2015, at the age of 90, after having survived Alick Isaacs (1921-1967) for almost five decades.

[Discovery and scientific investigation of a biological phenomenon].

A brief discussion is devoted to the 55-year long history of interferons and the contribution of domestic researchers to the study of this problem.

Historical developments in the research of interferon receptors.

Interferons (IFNs) were discovered 50 years ago independently by Isaacs and Lindemann and by Nagata and Kojima. When it was later realized that IFNs are active at very low concentrations, research began to determine how their powerful effects were generated from such a small initial signal. It has since been established that interferons, as well as all other cytokines, employ cell surface receptors to translate their presence in the serum to a potent cellular response to a viral infection. These receptor complexes are composed of multiple distinct glycosylated transmembrane polypeptides, a number of protein tyrosine kinases, and interact transiently with a large variety of other proteins including transcription factors, phosphatases, signaling repressors, and adaptor proteins coupling the receptor to alternative signaling pathways. Three major receptor complexes exist that are exclusive to each of three major classes of interferon. Even though the effects of each major class of interferon vary physiologically, each receptor complex interacts with its ligand in similar ways and activates similar signaling cascades. In this mini-review, we take a historical perspective at the major events in the characterization of interferon receptors, discussing interesting results that still need to be explained.

Interferon: the pathways of discovery I. Molecular and cellular aspects.

This historical account covers 50 years of seminal research work on interferon done since its discovery in 1957. Topics related to molecular structure, production and action of interferons are considered from the viewpoint of how our insights have expanded and deepened within the context of evolving tools and general knowledge in cellular and molecular biology. Lines of thought that linked each discovery to the next are expounded.

How to chase a red herring and come up with a smallmouth bass.

The collaboration between Alick Isaacs and myself started in the summer of 1956. Our initial project was to show, by electron microscopy, that interference between inactivated influenza virus and live virus involved the transfer of material from the interfering virus to the host cell. This approach failed for technical reasons. However, in the course of this work it appeared that more interfering activity remained in the system than we were entitled to expect. One possible explanation was that a substance, not identical with the initial interfering virus, was being generated. Subsequent experiments, aimed at checking this hypothesis, led to the description of interferon.

[Fundamentals of interferon system function in pathology and molecular biological peculiarities of interferon production].

Molecular biological peculiarities of interferon system function in PV-infected persons have been found. It is evident that the interferon production, anti-inflammatory cytokines and their receptors and also defensines play an important role in the mechanism of virus interaction with sensitive cells of macroorganism with development of pathological process. The new conception of expediency for the use of interferons and their inducers as the polyfunctional regulators with a broad spectrum of activity for the treatment of PV-infected patients was suggested. Patents for the method of treatment of PV-infected patients were obtained. New inducers of interferon as well as recombinant IFN-alpha-2b was developed. Our results were introduced in the medical practice.

[Interferon in the treatment of viral hepatitis. The interferon was discovered 50 years ago]. / Interferon a vírushepatitis kezelésében. 50 éve fedezték fel az interferont.

The interferons are heterogenic glycoproteins which are produced on the effect of virus infection, as immune answer, by the living cells. They were discovered half a century ago. They have antineoplastic, antiviral and immunomodulator effect. The names of interferons used in the therapy are nominated with Greek letters. This nomination shows their origins: the interferon-alpha originates from leucocytes, the interferon-beta does from fibroblasts and the interferon-gamma is produced as immune interferon by lymphocytes. In human medicine both natural and recombinant interferons are applied. The connection of polyethyleneglycol to interferons ensures their sustained effect. Nowadays they are applied in the therapy of chronic hepatitis B or C as well as in oncology to inhibit the neoplasm progression.

Historical review: Cytokines as therapeutics and targets of therapeutics.

Cytokine research has spawned the introduction of new therapies that have revolutionized the treatment of many important diseases. These therapeutic advances have resulted from two very different strategies. The first therapeutic strategy embodies the administration of purified, recombinant cytokines. The second relies on the administration of therapeutics that inhibit the harmful effects of upregulated, endogenous cytokines. Examples of successful cytokine therapeutics include hematopoietic growth factors (colony stimulating factors) and interferons. Prime examples of cytokine antagonists that have profoundly altered the treatment of some inflammatory disorders are agents that inhibit the effects of tumor necrosis factor (TNF). In this article, we highlight some of the studies that have been responsible for the introduction of cytokine and anti-cytokine therapies, with emphasis on the development of interferons and anti-TNF agents.

Interferon research: a brief history.

Interferons are the antiviral early inflammatory proteins produced in the cells in response to the infectious agents. The characterization of the interferon genes, their expression, and their function was advanced with the development of novel techniques in molecular and cellular biology. Using genetically modified mice revealed the critical role of the interferons in innate and acquired immune response. The critical steps and discovery that lead to the understanding of the interferon system and its role in the antiviral immune response are summarized in this chapter.

Interferon, PKR, virology, and genomics: what is past and what is next in the new millennium?

This paper provides an opportunity to reflect on my work in the interferon and cytokine field for the past almost 20 years and to look forward to the future. Winning the Milstein Award in 1999 was a great thrill. I briefly trace the history of my career from New York City to Seattle, leading up to the Paris award, and then look forward to the future that is full of promise because of the near-infinite power of genomics, computers, and other new technologies.

[Interferons (40 years since their discovery)]. / Interferony (k 40-letiiu otkrytiia).

Reviews the 40-year history of discovery and study of interferons. Traces the route from the first experimental observation to scientific interpretation of the phenomenon and its subsequent biological cognition. Pays special attention to modern stage in clinical use of interferons and their inductors and the contribution of Russian scientists to the problem.