Cytokine & Growth Factor Reviews 26 (2015) 99–101
Contents lists available at ScienceDirect
Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr
On intuition and the discovery of interferon Ion Gresser Centre National de Recherche, France
1. Intuition Intuition is often an essential component of any discovery. Although the solution to a problem seems to appear suddenly, it is often preceeded by a very long period of thought, work and gestation. This is illustrated by the following example, which though outside of the field of interferon, still bears some striking similarities. Otto Loewi, a German biochemist, received the Nobel Prize in 1936 for discovering: ‘‘The Chemical Transmission of Nerve Action’’ [1]. Until 1921, it was not known how the simple excitation of a nerve either stimulated or inhibited a target organ such as the heart. It was thought that there was a direct effect of the stimulated nerve fibre on the effector organ. However, it was also known that certain drugs mimicked the effects of nerve stimulation on the heart. In 1903, Loewi suggested that the chemical agents contained in these drugs might also be present at the nerve terminals, and that nerve stimulation might initiate the synthesis or secretion of a chemical which would then act on the muscle or gland. But as he could not think of an experiment to test this hypothesis he laid the idea aside. Years later, for quite different purposes, Loewi designed an experiment in which 2 frog hearts were kept beating in salt solution to determine whether the hearts secreted any chemical substances. Two years later, Loewi had a dream for an experiment, awoke, jotted down some notes and fell asleep. In the morning, he could not decipher his notes. The next night he had the same dream. It was the design of an experiment to determine whether or not the hypothesis of chemical transmission of nerve stimulation was correct. He got up, went to the laboratory at 3 in the morning and performed the following experiment: He excited the inhibitory vagus nerve of a frog’s heart which was bathed in a salt solution, and as expected the heart slowed. He then removed the salt solution and transferred it to a heart whose vagus nerve had been previously transected. The heart slowed down as if its non-existent vagus nerve had been stimulated [1,2]. The experiment showed that nerve stimulation indeed induced the release of a soluble factor(s) that mediated the effects of nerve stimulation on the target organ. I think that there is an analogy
E-mail address: [email protected]. http://dx.doi.org/10.1016/j.cytogfr.2014.11.006 1359-6101/ß 2014 Published by Elsevier Ltd.
between this discovery and the finding 20 years later, that interference between viruses was not a direct interaction, but was also mediated in most instances by a soluble factor ‘‘The Interferon’’. 2. Viral interference The Discovery of Interferon stemmed from the phenomenon of viral interference in which infection of a tissue or organism with one virus interfered with the multiplication of a related or unrelated second virus. This phenomenon which intrigued and puzzled many virologists had first been described for plant viruses in 1929 and for animal viruses in 1935. Some of the early work on viral interference is summarized in Fig. 1. Several points can be stressed: (1) In the experiments of Magrassi and Hoskins two strains of the same virus, neurotropic and viscerotropic were used; (2) Findlay and MacCullum used a different inducing virus from the challenge virus; (3) the phenomenon occurs in chick embryos, tissue culture or animals. (4) Noninfectious virus (influenza) also interfered with live influenza virus Henle, proposed various hypotheses to explain viral interference [3] (Fig. 2). At the time, hypotheses 3, 4, and 5 were considered the most likely. There were, however, some investigators who envisaged ‘‘hypothesis 6’’: the ‘‘antiviral activity of some product resulting from the primary infection’’ (i.e. interferon). For example: Vieuchange and Galli described a ‘‘neutralizing factor of vaccinia virus which was not antibody’’ [4]; Sven Gard working in Sweden in 1944 found a virus inhibitor which was ‘‘distinct from antibody; does not combine with the virus and acts on the cell’’. And in the Summary he states: ‘‘It is most probable, therefore, that the inhibitor interferes in the mechanisms of virus multiplication in the interior of the cell’’ [5]; Lennette and Koprowski specifically looked for the presence of antiviral substances in infected tissue cultures. Although some of their results now seem to suggest the presence of a viral inhibitor, the authors stated in their Summary that ‘‘non specific anti-viral substances were not present’’ [6]; Nagano and Kojima, in 1954, concluded that the supernatant of centrifuged vaccinia virus infected rabbit tissue contained a UV resistant viral inhibitor [7]. In 1958, they published more details on the production of their ‘‘facteur inhibiteur’’ [8]. I think it should be stressed that in all these attempts, the concentration of antiviral substances, if present, must have been very low.
I. Gresser / Cytokine & Growth Factor Reviews 26 (2015) 99–101
100
INTERFERFENCE BETWEEN ANIMAL VIRUSES
VARIOUS HYPOTHESES PROPOSED TO EXPLAIN VIRAL INTERFERENCE
MAGRASSI
1935
HERPES SIMPLEX
HOSKINS
1935
YELLOW FEVER
MONKEYS
1) PREVENTION OF SPREAD OF THE EXCLUDED VIRUS
FINDLAY MACCULLUM
1937
RIFT VALLEY YELLOW FEVER
MONKEYS
2) EXHAUSTION OF METABOLITES BY THE FIRST VIRUS
DALLDORF DOUGLAS
1938
LCM POLIOMYELITIS
MICE
3) BLOCKADE OR DESTRUCTION OF CELL RECEPTORS USED BY EITHER VIRUS
JUNGEBLUT SANDERS
1940
POLIOMYELITIS
MONKEYS
4) PREVENTION OF PENETRATION OF THE EXCLUDED VIRUS DUE TO CHANGES IN THE CELL SURFACE
ANDREWES
1942
INFLUENZA
TISSUE CULTURE
5) BLOCKADE OF/OR COMPETITION FOR A”KEY ENZYME” WITHIN THE HOST CELL
SCHLESINGER
1943
VIRUS III SHOPE FIBROMA
RABBITS
6) ANTIVIRAL ACTIVITY OF SOME PRODUCT RESULTING FROM THE PRIMARY INFECTION
HENLE-HENLE
1943
INACTIVE FLU ACTIVE FLU
CHICK EMBRYO
Fig. 2. Various hypotheses proposed to explain viral interference.
ISAACS EDNEY
1950
INACTIVE FLU ACTIVE FLU
CHICK EMBRYO
RABBITS
Fig. 1. Interferfence between animal viruses.
All these experiments showed that viral interference was perceived as a fundamental process that might lead to a better understanding of viral infections. Although many competent virologists had been working at the problem for many years, the explanation remained elusive.
3. Discovery of interferon In June 1956, Jean Lindenmann came to Mill Hill (London) to spend a post-doctoral year with Christopher Andrewes. He had been working in Zurich on viral interference using influenza virus and knew of Isaacs’ work with Edney on the same subject. When the two met by chance, they decided to work together, repeating the experimental model initiated in Zurich, using heat inactivated influenza virus absorbed to erythrocytes to interfere with active influenza virus [9]. A number of the experiments gave puzzling results and were not in accord with Isaacs’ experience and predictions. He became
intrigued by the possibility that a new interfering activity was being produced by the pieces of chick chorio allantoic membranes incubated with heat inactivated influenza virus. Lindenmann began referring to the ‘‘mysterious interfering substance as ‘‘The Interferon’’ and Isaacs’ notebook entry of 6 November 1956 starts with the sentence ‘‘In Search of an Interferon’’ [10]. As Lindenmann was to say years later: ‘‘We did not proceed systematically, but according to intuition’’ [10]. Fig. 3 is a schematic representation of the original experiment taken from Bill Stewart’s book ‘‘The Interferon System’’ [11] showing that the nutrient medium of the chick embryo chorioallantoic membrane that had been incubated with the heatinactived influenza virus contained the crucial virus inhibitor. Isaacs and Lindenmann’s first 2 papers were published in the Proceedings of the Royal Society in 1957 [12,13]. At this point, Isaacs and Lindenmann had no clear idea of the nature of Interferon. They stated in the Discussion: ‘‘The data presented are too scanty to allow even the crudest guess as to interferon’s chemical nature’’. They favoured the possibility that interferon was probably a product of an abortive influenza virus infection (not neutralized by antibody, nor sedimented by ultracentrifugation); perhaps some small fragment within the heated virus or a cellular
Fig. 3. A schematic representation of the original experiment of Isaacs and Lindenmann [12].
I. Gresser / Cytokine & Growth Factor Reviews 26 (2015) 99–101
enzyme or possibly ‘‘a product newly synthesized by the allantoic membrane [13].’’ 4. Characterization of the interferon In characterizing the biologic and chemical properties of intereron, Isaacs and Derek Burke showed in 1958 that it was, in fact, a cell produced protein and clearly differed from the inducing inactivated virus [14]. There was, however, considerable scepticism within the scientific community as to their results and some well known scientists sometimes referred to interferon as ‘‘misinterpreton’’. In 1959, Monto Ho and John Enders published results on a similar antiviral factor named VIF (Viral Inhibitory Factor) produced from poliovirus infected human cells in culture [15]. The properties of VIF were similar to those of interferon and their report greatly helped to dispel doubts as to the existence of interferon. Between 1959 and 1961, Isaacs published a series of aricles, on the mode of action of interferon with Derek Burke [16]; its species specificity with David Tyrell [17]; its antiviral action in rabbits with Marguerite Westwood [18]; and its role in the recovery from viral infection in mice with Griselda Hitchcock [19] and chick embryos with Samuel Baron [20]. From the onset, Isaacs was also interested in the clinical application of interferon, and intiated preliminary clinical experiments with David Tyrell in which volunteers pretreated with interferon were vaccinated with cow-pox virus, or injected intranasally with common cold viruses [21]. Unfortunately, Alick Isaacs’ career was cut short by his untimely death in 1967 at the age of 45. 5. Afterward After his post-doctoral year, Jean Lindenmann returned to Zurich and subsequently went to Florida intending to leave interferon research. For many years he and his colleagues investigated the cause of the genetically determined specific resistance of A2G mice to influenza A virus [22]. They named the responsible gene Mx (for myxovirus). They had excluded interferon as the responsible factor, only to find in 1979 that they had been working on interferon all along. Interferon indeed mediated the enhanced resistance of A2G mice to influenza A virus [23]. If the scientific community remained sceptical for many years, doubting the experimental results and even the existence of interferon, they were certainly not prepared to accept results suggesting that interferon also exhibited pleotypic effects on cells, and that the antiviral action was only one way of measuring the biologic activity of interferon [24,25]. After all, interferon had been discovered by virologists and it exhibited marked antiviral activity in vitro and in vivo. Other effects on cells by interferon were-in their opinion-clearly due to other factors or ‘‘contaminants’’in the very crude interferon preparations available at the time. Eventually, however, the purification and cloning of interferon put an end to all doubts concerning the existence and multiple biologic actions of interferon [26].
101
References [1] Loewi O. The chemical transmission of nerve action. Nobel Lectures Physiology or Medicine 1922–1941. Amsterdam: Elsevier Publishing Co.; 1936. p. 416–29. [2] Koestler A. The act of creation. London: Hutchinson Et Co.; 1964. p. 203–7. [3] Henle W. Interference phenomena between animal viruses: a review. J Immunol 1950;64:203–36. [4] Vieuchange J, Galli F. Presence d’un facteur neutralisant dans la lesion cutane´e provoque´e par l’inoculation intradermique de virus vaccinal. Comptes Rendus de l’Academie des Sciences 1939;208:2031–3. [5] Gard S. Tissue immunity in mouse poliomyelitis. Acta Med Scand 1944;69:27–45. [6] Lennette EH, Koprowski H. Interference between viruses in tissue culture. J Exp Med 1946;83:195–219. [7] Nagano Y, Kojima Y. Pouvoir immunisant du virus vaccinal inacitve´ par des rayons ultraviolets. C R Soc Biol 1954;148:1700–2. [8] Nagano Y, Kojima Y. Inhibition de l’infection vaccinale par le virus homologue. C R Seances Soc Biol Filiales 1958;152:1627–30. [9] Mooser H, Lindenmann J. Homologe interferenz durch hitzeinaktiviertes, an erythrozyten absorbiertes influeza-B-virus. Experientia 1957;XIII:147–8. [10] Peters T. Shaping a new biologic factor, ‘‘the interferon’’ in room 215 of the National institute for medical research 1956/57. Stud Hist Phil Sci 1997;28:27–73. [11] Stewart WE. The interferon system. Vienna: Springer-Verlag; 1979. p. 1–421. [12] Isaacs A, Lindenmann J. Virus interference. 1. The interferon. Proc R Soc Lond Ser B 1957;147:258–67. [13] Isaacs A, Lindenmann J, Valentine RC. Virus interference. 2. Some properties of interferon. Proc R Soc Lond Ser B 1957;147:268–73. [14] Isaacs A, Burke DC. Mode of action of interferon. Nature 1958;182:1073–4. [15] Ho M, Enders JF. An inhibitor of viral activity appearing in infected cell cultures. Proc Natl Acad Sci U S A 1959;45:385–9. [16] Isaacs A, Burke DC. Viral interference and interferon. Br Med Bull 1959;15: 185–8. [17] Tyrell DA. Interferon produced by cultures of calf kidney cells. Nature 1959;184:452–3. [18] Isaacs A, Westwood MA. Inhibition by interferon of the growth of vaccinia virus in the rabbit skin. Lancet 1959;ii:324–5. [19] Isaacs A, Hitchcock G. Role of interferon in recovery from virus infections. Lancet 1960;ii:69–71. [20] Baron S, Isaacs A. Mechanism of recovery from viral infection in the chick embryo. Nature 1961;191:97–8. [21] Scientific Committee on Interferon: experiments with interferon in man. Lancet 1965;i:505–10. [22] Lindenmann J, Lane CA, Hobson D. The resistance of A2G mice to myxoviruses. J Immunol 1962;90:942–51. [23] Haller O, Arnheiter H, Gresser I, Lindenmann J. Genetically determined interferon-dependent resistance to influenza virus in mice. J Exp Med 1979;149:601–12. [24] Gresser I. On the varied biologic effects of interferon. Cell Immunol 1977;34: 406–15. [25] Gresser I. Wherefore interferon? J Leukoc Biol 1997;61:567–74. [26] Gresser I, De Maeyer-Guignard J, Tovey MG, De Maeyer E. Electrophoretically pure mouse interferon exerts multiple biologic effects. Proc Natl Acad Sci U S A 1979;76:5308–12. Dr. Ion Gresser received his M.D. degree from Yale Medical School in 1955 and was an intern in medicine at Bellevue Hospital in N.Y.C. 1955–1956. He served in the U.S. Army, 1956–1958, as Director of the Laboratory of Virus and Rickettsial Diseases at the 406th General Medical Laboratory in Japan. Dr. Gresserwas a resident in medicine at Bellevue Hospital in 1958–1959. He then spent the next 5 years in the laboratory of Professor John F. Enders in Boston working on interferon. In 1965, Dr. Gresseraccepted the position of Director of the Laboratory of Viral Oncology at the Institut de Recherches Scientifiques sur le Cancer, Villejuif, France. His research demonstrated that interferon treatment inhibited the evolution of several viral induced and spontaneous leukemias of mice, as well as transplanted non viral tumors. Subsequent results indicated that interferon was not exclusively an antiviral substance but exerted multiple biologic effects on cells. For the next 30 years his research team investigated the spectrum of the biologic effects of interferon and especially its effects on the immune system. Dr. Gresser retired in 1997, and became Directeur de Recherche Emeritus C.N.R.S.
Contents lists available at ScienceDirect
Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr
On intuition and the discovery of interferon Ion Gresser Centre National de Recherche, France
1. Intuition Intuition is often an essential component of any discovery. Although the solution to a problem seems to appear suddenly, it is often preceeded by a very long period of thought, work and gestation. This is illustrated by the following example, which though outside of the field of interferon, still bears some striking similarities. Otto Loewi, a German biochemist, received the Nobel Prize in 1936 for discovering: ‘‘The Chemical Transmission of Nerve Action’’ [1]. Until 1921, it was not known how the simple excitation of a nerve either stimulated or inhibited a target organ such as the heart. It was thought that there was a direct effect of the stimulated nerve fibre on the effector organ. However, it was also known that certain drugs mimicked the effects of nerve stimulation on the heart. In 1903, Loewi suggested that the chemical agents contained in these drugs might also be present at the nerve terminals, and that nerve stimulation might initiate the synthesis or secretion of a chemical which would then act on the muscle or gland. But as he could not think of an experiment to test this hypothesis he laid the idea aside. Years later, for quite different purposes, Loewi designed an experiment in which 2 frog hearts were kept beating in salt solution to determine whether the hearts secreted any chemical substances. Two years later, Loewi had a dream for an experiment, awoke, jotted down some notes and fell asleep. In the morning, he could not decipher his notes. The next night he had the same dream. It was the design of an experiment to determine whether or not the hypothesis of chemical transmission of nerve stimulation was correct. He got up, went to the laboratory at 3 in the morning and performed the following experiment: He excited the inhibitory vagus nerve of a frog’s heart which was bathed in a salt solution, and as expected the heart slowed. He then removed the salt solution and transferred it to a heart whose vagus nerve had been previously transected. The heart slowed down as if its non-existent vagus nerve had been stimulated [1,2]. The experiment showed that nerve stimulation indeed induced the release of a soluble factor(s) that mediated the effects of nerve stimulation on the target organ. I think that there is an analogy
E-mail address: [email protected]. http://dx.doi.org/10.1016/j.cytogfr.2014.11.006 1359-6101/ß 2014 Published by Elsevier Ltd.
between this discovery and the finding 20 years later, that interference between viruses was not a direct interaction, but was also mediated in most instances by a soluble factor ‘‘The Interferon’’. 2. Viral interference The Discovery of Interferon stemmed from the phenomenon of viral interference in which infection of a tissue or organism with one virus interfered with the multiplication of a related or unrelated second virus. This phenomenon which intrigued and puzzled many virologists had first been described for plant viruses in 1929 and for animal viruses in 1935. Some of the early work on viral interference is summarized in Fig. 1. Several points can be stressed: (1) In the experiments of Magrassi and Hoskins two strains of the same virus, neurotropic and viscerotropic were used; (2) Findlay and MacCullum used a different inducing virus from the challenge virus; (3) the phenomenon occurs in chick embryos, tissue culture or animals. (4) Noninfectious virus (influenza) also interfered with live influenza virus Henle, proposed various hypotheses to explain viral interference [3] (Fig. 2). At the time, hypotheses 3, 4, and 5 were considered the most likely. There were, however, some investigators who envisaged ‘‘hypothesis 6’’: the ‘‘antiviral activity of some product resulting from the primary infection’’ (i.e. interferon). For example: Vieuchange and Galli described a ‘‘neutralizing factor of vaccinia virus which was not antibody’’ [4]; Sven Gard working in Sweden in 1944 found a virus inhibitor which was ‘‘distinct from antibody; does not combine with the virus and acts on the cell’’. And in the Summary he states: ‘‘It is most probable, therefore, that the inhibitor interferes in the mechanisms of virus multiplication in the interior of the cell’’ [5]; Lennette and Koprowski specifically looked for the presence of antiviral substances in infected tissue cultures. Although some of their results now seem to suggest the presence of a viral inhibitor, the authors stated in their Summary that ‘‘non specific anti-viral substances were not present’’ [6]; Nagano and Kojima, in 1954, concluded that the supernatant of centrifuged vaccinia virus infected rabbit tissue contained a UV resistant viral inhibitor [7]. In 1958, they published more details on the production of their ‘‘facteur inhibiteur’’ [8]. I think it should be stressed that in all these attempts, the concentration of antiviral substances, if present, must have been very low.
I. Gresser / Cytokine & Growth Factor Reviews 26 (2015) 99–101
100
INTERFERFENCE BETWEEN ANIMAL VIRUSES
VARIOUS HYPOTHESES PROPOSED TO EXPLAIN VIRAL INTERFERENCE
MAGRASSI
1935
HERPES SIMPLEX
HOSKINS
1935
YELLOW FEVER
MONKEYS
1) PREVENTION OF SPREAD OF THE EXCLUDED VIRUS
FINDLAY MACCULLUM
1937
RIFT VALLEY YELLOW FEVER
MONKEYS
2) EXHAUSTION OF METABOLITES BY THE FIRST VIRUS
DALLDORF DOUGLAS
1938
LCM POLIOMYELITIS
MICE
3) BLOCKADE OR DESTRUCTION OF CELL RECEPTORS USED BY EITHER VIRUS
JUNGEBLUT SANDERS
1940
POLIOMYELITIS
MONKEYS
4) PREVENTION OF PENETRATION OF THE EXCLUDED VIRUS DUE TO CHANGES IN THE CELL SURFACE
ANDREWES
1942
INFLUENZA
TISSUE CULTURE
5) BLOCKADE OF/OR COMPETITION FOR A”KEY ENZYME” WITHIN THE HOST CELL
SCHLESINGER
1943
VIRUS III SHOPE FIBROMA
RABBITS
6) ANTIVIRAL ACTIVITY OF SOME PRODUCT RESULTING FROM THE PRIMARY INFECTION
HENLE-HENLE
1943
INACTIVE FLU ACTIVE FLU
CHICK EMBRYO
Fig. 2. Various hypotheses proposed to explain viral interference.
ISAACS EDNEY
1950
INACTIVE FLU ACTIVE FLU
CHICK EMBRYO
RABBITS
Fig. 1. Interferfence between animal viruses.
All these experiments showed that viral interference was perceived as a fundamental process that might lead to a better understanding of viral infections. Although many competent virologists had been working at the problem for many years, the explanation remained elusive.
3. Discovery of interferon In June 1956, Jean Lindenmann came to Mill Hill (London) to spend a post-doctoral year with Christopher Andrewes. He had been working in Zurich on viral interference using influenza virus and knew of Isaacs’ work with Edney on the same subject. When the two met by chance, they decided to work together, repeating the experimental model initiated in Zurich, using heat inactivated influenza virus absorbed to erythrocytes to interfere with active influenza virus [9]. A number of the experiments gave puzzling results and were not in accord with Isaacs’ experience and predictions. He became
intrigued by the possibility that a new interfering activity was being produced by the pieces of chick chorio allantoic membranes incubated with heat inactivated influenza virus. Lindenmann began referring to the ‘‘mysterious interfering substance as ‘‘The Interferon’’ and Isaacs’ notebook entry of 6 November 1956 starts with the sentence ‘‘In Search of an Interferon’’ [10]. As Lindenmann was to say years later: ‘‘We did not proceed systematically, but according to intuition’’ [10]. Fig. 3 is a schematic representation of the original experiment taken from Bill Stewart’s book ‘‘The Interferon System’’ [11] showing that the nutrient medium of the chick embryo chorioallantoic membrane that had been incubated with the heatinactived influenza virus contained the crucial virus inhibitor. Isaacs and Lindenmann’s first 2 papers were published in the Proceedings of the Royal Society in 1957 [12,13]. At this point, Isaacs and Lindenmann had no clear idea of the nature of Interferon. They stated in the Discussion: ‘‘The data presented are too scanty to allow even the crudest guess as to interferon’s chemical nature’’. They favoured the possibility that interferon was probably a product of an abortive influenza virus infection (not neutralized by antibody, nor sedimented by ultracentrifugation); perhaps some small fragment within the heated virus or a cellular
Fig. 3. A schematic representation of the original experiment of Isaacs and Lindenmann [12].
I. Gresser / Cytokine & Growth Factor Reviews 26 (2015) 99–101
enzyme or possibly ‘‘a product newly synthesized by the allantoic membrane [13].’’ 4. Characterization of the interferon In characterizing the biologic and chemical properties of intereron, Isaacs and Derek Burke showed in 1958 that it was, in fact, a cell produced protein and clearly differed from the inducing inactivated virus [14]. There was, however, considerable scepticism within the scientific community as to their results and some well known scientists sometimes referred to interferon as ‘‘misinterpreton’’. In 1959, Monto Ho and John Enders published results on a similar antiviral factor named VIF (Viral Inhibitory Factor) produced from poliovirus infected human cells in culture [15]. The properties of VIF were similar to those of interferon and their report greatly helped to dispel doubts as to the existence of interferon. Between 1959 and 1961, Isaacs published a series of aricles, on the mode of action of interferon with Derek Burke [16]; its species specificity with David Tyrell [17]; its antiviral action in rabbits with Marguerite Westwood [18]; and its role in the recovery from viral infection in mice with Griselda Hitchcock [19] and chick embryos with Samuel Baron [20]. From the onset, Isaacs was also interested in the clinical application of interferon, and intiated preliminary clinical experiments with David Tyrell in which volunteers pretreated with interferon were vaccinated with cow-pox virus, or injected intranasally with common cold viruses [21]. Unfortunately, Alick Isaacs’ career was cut short by his untimely death in 1967 at the age of 45. 5. Afterward After his post-doctoral year, Jean Lindenmann returned to Zurich and subsequently went to Florida intending to leave interferon research. For many years he and his colleagues investigated the cause of the genetically determined specific resistance of A2G mice to influenza A virus [22]. They named the responsible gene Mx (for myxovirus). They had excluded interferon as the responsible factor, only to find in 1979 that they had been working on interferon all along. Interferon indeed mediated the enhanced resistance of A2G mice to influenza A virus [23]. If the scientific community remained sceptical for many years, doubting the experimental results and even the existence of interferon, they were certainly not prepared to accept results suggesting that interferon also exhibited pleotypic effects on cells, and that the antiviral action was only one way of measuring the biologic activity of interferon [24,25]. After all, interferon had been discovered by virologists and it exhibited marked antiviral activity in vitro and in vivo. Other effects on cells by interferon were-in their opinion-clearly due to other factors or ‘‘contaminants’’in the very crude interferon preparations available at the time. Eventually, however, the purification and cloning of interferon put an end to all doubts concerning the existence and multiple biologic actions of interferon [26].
101
References [1] Loewi O. The chemical transmission of nerve action. Nobel Lectures Physiology or Medicine 1922–1941. Amsterdam: Elsevier Publishing Co.; 1936. p. 416–29. [2] Koestler A. The act of creation. London: Hutchinson Et Co.; 1964. p. 203–7. [3] Henle W. Interference phenomena between animal viruses: a review. J Immunol 1950;64:203–36. [4] Vieuchange J, Galli F. Presence d’un facteur neutralisant dans la lesion cutane´e provoque´e par l’inoculation intradermique de virus vaccinal. Comptes Rendus de l’Academie des Sciences 1939;208:2031–3. [5] Gard S. Tissue immunity in mouse poliomyelitis. Acta Med Scand 1944;69:27–45. [6] Lennette EH, Koprowski H. Interference between viruses in tissue culture. J Exp Med 1946;83:195–219. [7] Nagano Y, Kojima Y. Pouvoir immunisant du virus vaccinal inacitve´ par des rayons ultraviolets. C R Soc Biol 1954;148:1700–2. [8] Nagano Y, Kojima Y. Inhibition de l’infection vaccinale par le virus homologue. C R Seances Soc Biol Filiales 1958;152:1627–30. [9] Mooser H, Lindenmann J. Homologe interferenz durch hitzeinaktiviertes, an erythrozyten absorbiertes influeza-B-virus. Experientia 1957;XIII:147–8. [10] Peters T. Shaping a new biologic factor, ‘‘the interferon’’ in room 215 of the National institute for medical research 1956/57. Stud Hist Phil Sci 1997;28:27–73. [11] Stewart WE. The interferon system. Vienna: Springer-Verlag; 1979. p. 1–421. [12] Isaacs A, Lindenmann J. Virus interference. 1. The interferon. Proc R Soc Lond Ser B 1957;147:258–67. [13] Isaacs A, Lindenmann J, Valentine RC. Virus interference. 2. Some properties of interferon. Proc R Soc Lond Ser B 1957;147:268–73. [14] Isaacs A, Burke DC. Mode of action of interferon. Nature 1958;182:1073–4. [15] Ho M, Enders JF. An inhibitor of viral activity appearing in infected cell cultures. Proc Natl Acad Sci U S A 1959;45:385–9. [16] Isaacs A, Burke DC. Viral interference and interferon. Br Med Bull 1959;15: 185–8. [17] Tyrell DA. Interferon produced by cultures of calf kidney cells. Nature 1959;184:452–3. [18] Isaacs A, Westwood MA. Inhibition by interferon of the growth of vaccinia virus in the rabbit skin. Lancet 1959;ii:324–5. [19] Isaacs A, Hitchcock G. Role of interferon in recovery from virus infections. Lancet 1960;ii:69–71. [20] Baron S, Isaacs A. Mechanism of recovery from viral infection in the chick embryo. Nature 1961;191:97–8. [21] Scientific Committee on Interferon: experiments with interferon in man. Lancet 1965;i:505–10. [22] Lindenmann J, Lane CA, Hobson D. The resistance of A2G mice to myxoviruses. J Immunol 1962;90:942–51. [23] Haller O, Arnheiter H, Gresser I, Lindenmann J. Genetically determined interferon-dependent resistance to influenza virus in mice. J Exp Med 1979;149:601–12. [24] Gresser I. On the varied biologic effects of interferon. Cell Immunol 1977;34: 406–15. [25] Gresser I. Wherefore interferon? J Leukoc Biol 1997;61:567–74. [26] Gresser I, De Maeyer-Guignard J, Tovey MG, De Maeyer E. Electrophoretically pure mouse interferon exerts multiple biologic effects. Proc Natl Acad Sci U S A 1979;76:5308–12. Dr. Ion Gresser received his M.D. degree from Yale Medical School in 1955 and was an intern in medicine at Bellevue Hospital in N.Y.C. 1955–1956. He served in the U.S. Army, 1956–1958, as Director of the Laboratory of Virus and Rickettsial Diseases at the 406th General Medical Laboratory in Japan. Dr. Gresserwas a resident in medicine at Bellevue Hospital in 1958–1959. He then spent the next 5 years in the laboratory of Professor John F. Enders in Boston working on interferon. In 1965, Dr. Gresseraccepted the position of Director of the Laboratory of Viral Oncology at the Institut de Recherches Scientifiques sur le Cancer, Villejuif, France. His research demonstrated that interferon treatment inhibited the evolution of several viral induced and spontaneous leukemias of mice, as well as transplanted non viral tumors. Subsequent results indicated that interferon was not exclusively an antiviral substance but exerted multiple biologic effects on cells. For the next 30 years his research team investigated the spectrum of the biologic effects of interferon and especially its effects on the immune system. Dr. Gresser retired in 1997, and became Directeur de Recherche Emeritus C.N.R.S.
