Editing Interferon (section)

==History==
{{primary sources section|find=Interferon|find2=history|date=July 2014}}
[[File:SidneyPestka NationalMedalOfTech.jpg|thumbnail|[[Sidney Pestka]] of [[Rutgers University]], seen here receiving the [[National Medal of Technology]].]]

Interferons were first described in 1957 by [[Alick Isaacs]] and [[Jean Lindenmann]] at the [[National Institute for Medical Research]] in London;<ref name=nytimes>{{cite news | vauthors = Kolata G |title=Jean Lindenmann, Who Made Interferon His Life's Work, Is Dead at 90 |url=https://www.nytimes.com/2015/01/23/us/jean-lindenmann-made-interferon-his-lifes-work-is-dead-at-90.html?_r=0 |work=[[The New York Times]] |date=2015-01-22 |access-date=2015-02-12 |archive-date=2019-12-27 |archive-url=https://web.archive.org/web/20191227123436/https://www.nytimes.com/2015/01/23/us/jean-lindenmann-made-interferon-his-lifes-work-is-dead-at-90.html?_r=0 |url-status=live }}</ref><ref name=Issacs>{{cite journal | vauthors = Isaacs A, Lindenmann J | title = Virus interference. I. The interferon | journal = Proceedings of the Royal Society of London. Series B, Biological Sciences | volume = 147 | issue = 927 | pages = 258–267 | date = September 1957 | pmid = 13465720 | doi = 10.1098/rspb.1957.0048 | s2cid = 202574492 | bibcode = 1957RSPSB.147..258I }}</ref><ref name=pestka>{{cite journal | vauthors = Pestka S | title = The interferons: 50 years after their discovery, there is much more to learn | journal = The Journal of Biological Chemistry | volume = 282 | issue = 28 | pages = 20047–20051 | date = July 2007 | pmid = 17502369 | doi = 10.1074/jbc.R700004200 | doi-access = free }}</ref> the discovery was a result of their studies of [[viral interference]]. Viral interference refers to the inhibition of virus growth caused by previous exposure of cells to an active or a heat-inactivated virus. Isaacs and Lindenmann were working with a system that involved the inhibition of the growth of live influenza virus in chicken embryo chorioallantoic membranes by heat-inactivated influenza virus. Their experiments revealed that this interference was mediated by a protein released by cells in the heat-inactivated influenza virus-treated membranes. They published their results in 1957 naming the antiviral factor they had discovered ''interferon''.<ref name=Issacs /> The findings of Isaacs and Lindenmann have been widely confirmed and corroborated in the literature.<ref>{{cite book| vauthors = Stewart II WE |title=The Interferon System|page=1|date=2013-04-17|publisher=Springer Science & Business Media|isbn=978-3-7091-3432-0}}</ref>

Furthermore, others may have made observations on interferons before the 1957 publication of Isaacs and Lindenmann. For example, during research to produce a more efficient [[vaccine]] for [[smallpox]], Yasu-ichi Nagano and Yasuhiko Kojima—two Japanese [[virology|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 [[inoculate]]d 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 [[Homogenization (biology)|homogenate]]s.<ref>{{cite journal | vauthors = Nagano Y, Kojima Y | title = [Immunizing property of vaccinia virus inactivated by ultraviolets rays] | language = fr | journal = Comptes Rendus des Séances de la Société de Biologie et de Ses Filiales | volume = 148 | issue = 19–20 | pages = 1700–1702 | date = October 1954 | pmid = 14364998 | url = https://gallica.bnf.fr/ark:/12148/bpt6k9748814w/f1726.item | trans-title = Immunizing property of vaccinia virus inactivated by ultraviolets rays }}</ref> Independently, Monto Ho, in [[John Franklin Enders|John Enders]]'s lab, observed in 1957 that attenuated poliovirus conferred a species specific anti-viral effect in human amniotic cell cultures. They described these observations in a 1959 publication, naming the responsible factor ''viral inhibitory factor'' (VIF).<ref name="pmid16590396">{{cite journal | vauthors = Ho M, Enders JF | title = An Inhibitor of Viral Activity Appearing in Infected Cell Cultures | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 45 | issue = 3 | pages = 385–389 | date = March 1959 | pmid = 16590396 | pmc = 222571 | doi = 10.1073/pnas.45.3.385 | doi-access = free | bibcode = 1959PNAS...45..385H }}</ref> 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.<ref name="pmid4346649">{{cite journal | vauthors = Tan YH, Tischfield J, Ruddle FH | title = The linkage of genes for the human interferon-induced antiviral protein and indophenol oxidase-B traits to chromosome G-21 | journal = The Journal of Experimental Medicine | volume = 137 | issue = 2 | pages = 317–330 | date = February 1973 | pmid = 4346649 | pmc = 2139494 | doi = 10.1084/jem.137.2.317 }}</ref><ref name="pmid176593">{{cite journal | vauthors = Tan YH | title = Chromosome 21 and the cell growth inhibitory effect of human interferon preparations | journal = Nature | volume = 260 | issue = 5547 | pages = 141–143 | date = March 1976 | pmid = 176593 | doi = 10.1038/260141a0 | s2cid = 4287343 | bibcode = 1976Natur.260..141T }}</ref><ref name="pmid460428">{{cite journal | vauthors = Meager A, Graves H, Burke DC, Swallow DM | title = Involvement of a gene on chromosome 9 in human fibroblast interferon production | journal = Nature | volume = 280 | issue = 5722 | pages = 493–495 | date = August 1979 | pmid = 460428 | doi = 10.1038/280493a0 | s2cid = 4315307 | bibcode = 1979Natur.280..493M }}</ref> The purification of human beta interferon did not occur until 1977. 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.<ref name="pmid678325">{{cite journal | vauthors = Berthold W, Tan C, Tan YH | title = Chemical modifications of tyrosyl residue(s) and action of human-fibroblast interferon | journal = European Journal of Biochemistry | volume = 87 | issue = 2 | pages = 367–370 | date = June 1978 | pmid = 678325 | doi = 10.1111/j.1432-1033.1978.tb12385.x | doi-access = free }}</ref><ref name="pmid670186">{{cite journal | vauthors = Berthold W, Tan C, Tan YH | title = Purification and in vitro labeling of interferon from a human fibroblastoid cell line | journal = The Journal of Biological Chemistry | volume = 253 | issue = 14 | pages = 5206–5212 | date = July 1978 | pmid = 670186 | doi = 10.1016/S0021-9258(17)34678-1 | doi-access = free }}</ref> Tan's laboratory isolated sufficient amounts of human beta interferon to perform the first amino acid, sugar composition and N-terminal analyses.<ref name="Tan_1979">{{cite journal | vauthors = Tan YH, Barakat F, Berthold W, Smith-Johannsen H, Tan C | title = The isolation and amino acid/sugar composition of human fibroblastoid interferon | journal = The Journal of Biological Chemistry | volume = 254 | issue = 16 | pages = 8067–8073 | date = August 1979 | pmid = 468807 | doi = 10.1016/S0021-9258(18)36051-4 | doi-access = free }}</ref> They showed that human beta interferon was an unusually hydrophobic glycoprotein. This explained the large loss of interferon activity when preparations were transferred from test tube to test tube or from vessel to vessel during purification. The analyses showed the reality of interferon activity by chemical verification.<ref name="Tan_1979"/><ref name="pmid7352260">{{cite journal | vauthors = Zoon KC, Smith ME, Bridgen PJ, Anfinsen CB, Hunkapiller MW, Hood LE | title = Amino terminal sequence of the major component of human lymphoblastoid interferon | journal = Science | volume = 207 | issue = 4430 | pages = 527–528 | date = February 1980 | pmid = 7352260 | doi = 10.1126/science.7352260 | bibcode = 1980Sci...207..527Z }}</ref><ref name="pmid6157401">{{cite journal | vauthors = Okamura H, Berthold W, Hood L, Hunkapiller M, Inoue M, Smith-Johannsen H, Tan YH | title = Human fibroblastoid interferon: immunosorbent column chromatography and N-terminal amino acid sequence | journal = Biochemistry | volume = 19 | issue = 16 | pages = 3831–3835 | date = August 1980 | pmid = 6157401 | doi = 10.1021/bi00557a028 }}</ref><ref name="pmid7352259">{{cite journal | vauthors = Knight E, Hunkapiller MW, Korant BD, Hardy RW, Hood LE | title = Human fibroblast interferon: amino acid analysis and amino terminal amino acid sequence | journal = Science | volume = 207 | issue = 4430 | pages = 525–526 | date = February 1980 | pmid = 7352259 | doi = 10.1126/science.7352259 | bibcode = 1980Sci...207..525K }}</ref> 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.<ref name=pestka /> By the early 1980s, genes for these interferons had been cloned, adding further definitive proof that interferons were responsible for interfering with viral replication.<ref name="pmid6164058">{{cite journal | vauthors = Weissenbach J, Chernajovsky Y, Zeevi M, Shulman L, Soreq H, Nir U, Wallach D, Perricaudet M, Tiollais P, Revel M | title = Two interferon mRNAs in human fibroblasts: in vitro translation and Escherichia coli cloning studies | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 12 | pages = 7152–7156 | date = December 1980 | pmid = 6164058 | pmc = 350459 | doi = 10.1073/pnas.77.12.7152 | doi-access = free | bibcode = 1980PNAS...77.7152W }}</ref><ref name="pmid6159625">{{cite journal | vauthors = Taniguchi T, Fujii-Kuriyama Y, Muramatsu M | title = Molecular cloning of human interferon cDNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 7 | pages = 4003–4006 | date = July 1980 | pmid = 6159625 | pmc = 349756 | doi = 10.1073/pnas.77.7.4003 | doi-access = free | bibcode = 1980PNAS...77.4003T }}</ref>  Gene cloning also confirmed that IFN-α was encoded by a family of many related genes.<ref name="pmid6159536">{{cite journal | vauthors = Nagata S, Mantei N, Weissmann C | title = The structure of one of the eight or more distinct chromosomal genes for human interferon-alpha | journal = Nature | volume = 287 | issue = 5781 | pages = 401–408 | date = October 1980 | pmid = 6159536 | doi = 10.1038/287401a0 | s2cid = 29500779 | bibcode = 1980Natur.287..401N }}</ref>  The type II IFN (IFN-γ) gene was also isolated around this time.<ref name="pmid6180322">{{cite journal | vauthors = Gray PW, Goeddel DV | title = Structure of the human immune interferon gene | journal = Nature | volume = 298 | issue = 5877 | pages = 859–863 | date = August 1982 | pmid = 6180322 | doi = 10.1038/298859a0 | s2cid = 4275528 | bibcode = 1982Natur.298..859G }}</ref>

Interferon was first synthesized manually at [[Rockefeller University]] in the lab of Dr. [[Bruce Merrifield]], using [[solid phase peptide synthesis]], one amino acid at a time. He later won the Nobel Prize in chemistry. Interferon was scarce and expensive until 1980, when the interferon [[gene]] was inserted into [[bacterium|bacteria]] using [[recombinant DNA technology]], allowing mass cultivation and purification from [[Microbiological culture#Bacterial culture|bacterial cultures]]<ref>{{cite journal | vauthors = Nagata S, Taira H, Hall A, Johnsrud L, Streuli M, Ecsödi J, Boll W, Cantell K, Weissmann C | title = Synthesis in E. coli of a polypeptide with human leukocyte interferon activity | journal = Nature | volume = 284 | issue = 5754 | pages = 316–320 | date = March 1980 | pmid = 6987533 | doi = 10.1038/284316a0 | s2cid = 4310807 | bibcode = 1980Natur.284..316N }}</ref> or derived from [[yeast]]s. Interferon can also be produced by recombinant mammalian cells.<ref>{{cite patent | inventor = Tan YH, Hong WJ | assign = Institute of Molecular and Cell Biology
 | title = Gene expression in mammalian cells. | country = US | number = 6207146 | gdate = 27 April 2001 | status = patent }}</ref>
Before the early 1970s, large scale production of human interferon had been pioneered by Kari Cantell. He produced large amounts of human alpha interferon from large quantities of human white blood cells collected by the Finnish Blood Bank.<ref>{{Cite book | vauthors = Cantell K | title = The story of interferon: the ups and downs in the life of a scientis | date = 1998 | publisher = World Scientific | location = Singapore; New York | isbn = 978-981-02-3148-4  }}</ref> Large amounts of human beta interferon were made by superinducing the beta interferon gene in human fibroblast cells.<ref name="pmid5272327">{{cite journal | vauthors = Tan YH, Armstrong JA, Ke YH, Ho M | title = Regulation of cellular interferon production: enhancement by antimetabolites | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 67 | issue = 1 | pages = 464–471 | date = September 1970 | pmid = 5272327 | pmc = 283227 | doi = 10.1073/pnas.67.1.464 | doi-access = free | bibcode = 1970PNAS...67..464T }}</ref><ref>{{cite patent | inventor = Ho M, Armstrong JA, Ke YH, Tan YH | title =  Interferon Production | country = US | status = patent | number = 3773924 | gdate = 20 November 1973 }}</ref>

Cantell's and Tan's methods of making large amounts of natural interferon were critical for chemical characterisation, clinical trials and the preparation of small amounts of interferon messenger RNA to clone the human alpha and beta interferon genes. The superinduced human beta interferon messenger RNA was prepared by Tan's lab for [[Cetus Corporation|Cetus]]. to clone the human beta interferon gene in 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.