Editing Prion (section)

== History ==
In the 18th and 19th centuries, exportation of sheep from Spain was observed to coincide with a disease called [[scrapie]]. This disease caused the affected animals to ''"lie down, bite at their feet and legs, rub their backs against posts, fail to thrive, stop feeding and finally become lame"''.<ref>{{Cite web|title=How Prions Came to Be: A Brief History – Infectious Disease: Superbugs, Science, & Society|url=https://sites.duke.edu/superbugs/module-6/prions-mad-cow-disease-when-proteins-go-bad/how-prions-came-to-be-a-brief-history/|access-date=2021-09-17|language=en-US|archive-date=2021-09-17|archive-url=https://web.archive.org/web/20210917234712/https://sites.duke.edu/superbugs/module-6/prions-mad-cow-disease-when-proteins-go-bad/how-prions-came-to-be-a-brief-history/|url-status=live}}</ref> The disease was also observed to have the long incubation period that is a key characteristic of [[Transmissible spongiform encephalopathy|transmissible spongiform encephalopathies (TSEs)]]. Although the cause of scrapie was not known back then, it is probably the first transmissible spongiform encephalopathy to be recorded.<ref>{{cite journal | vauthors = Ness A, Aiken J, McKenzie D | title = Sheep scrapie and deer rabies in England prior to 1800 | journal = Prion | volume = 17 | issue = 1 | pages = 7–15 | date = December 2023 | pmid = 36654484 | pmc = 9858414 | doi = 10.1080/19336896.2023.2166749 }}</ref>

In the 1950s, [[Daniel Carleton Gajdusek|Carleton Gajdusek]] began research which eventually showed that [[Kuru (disease)|kuru]] could be transmitted to chimpanzees by what was possibly a new infectious agent, work for which he eventually won the 1976 [[Nobel Prize]]. During the 1960s, two London-based researchers, radiation biologist [[Tikvah Alper]] and biophysicist [[John Stanley Griffith]], developed the hypothesis that the [[transmissible spongiform encephalopathy|transmissible spongiform encephalopathies]] are caused by an infectious agent consisting solely of proteins.<ref>{{cite journal | vauthors = Alper T, Cramp WA, Haig DA, Clarke MC | title = Does the agent of scrapie replicate without nucleic acid? | journal = Nature | volume = 214 | issue = 5090 | pages = 764–6 | date = May 1967 | pmid = 4963878 | doi = 10.1038/214764a0 | s2cid = 4195902 | bibcode = 1967Natur.214..764A }}</ref><ref name=Griffith67>{{cite journal | vauthors = Griffith JS | title = Self-replication and scrapie | journal = Nature | volume = 215 | issue = 5105 | pages = 1043–4 | date = September 1967 | pmid = 4964084 | doi = 10.1038/2151043a0 | s2cid = 4171947 | bibcode = 1967Natur.215.1043G }}</ref> Earlier investigations by [[E.J. Field]] into [[scrapie]] and kuru had found evidence for the transfer of pathologically inert polysaccharides that only become infectious post-transfer, in the new host.<ref name="pmid5950508">{{cite journal | vauthors = Field EJ | title = Transmission experiments with multiple sclerosis: an interim report | journal = British Medical Journal | volume = 2 | issue = 5513 | pages = 564–5 | date = September 1966 | pmid = 5950508 | pmc = 1943767 | doi = 10.1136/bmj.2.5513.564 }}</ref><ref name="pmid4175093">{{cite journal | vauthors = Adams DH, Field EJ | title = The infective process in scrapie | journal = Lancet | volume = 2 | issue = 7570 | pages = 714–6 | date = September 1968 | pmid = 4175093 | doi = 10.1016/s0140-6736(68)90754-x }}</ref> Alper and Griffith wanted to account for the discovery that the mysterious infectious agent causing the diseases scrapie and [[Creutzfeldt–Jakob disease]] resisted [[ionizing radiation]].<ref>{{cite journal | vauthors = Field EJ, Farmer F, Caspary EA, Joyce G | title = Susceptibility of scrapie agent to ionizing radiation | journal = Nature | volume = 222 | issue = 5188 | pages = 90–91 | date = April 1969 | pmid = 4975649 | doi = 10.1038/222090a0 | series = 5188 | s2cid = 4195610 | bibcode = 1969Natur.222...90F }}</ref> Griffith proposed three ways in which a protein could be a [[pathogen]].<ref name=Griffith67/>

In the first [[hypothesis]], he suggested that if the protein is the product of a normally suppressed [[gene]], and introducing the protein could induce the gene's expression, that is, wake the dormant gene up, then the result would be a process indistinguishable from replication, as the gene's expression would produce the protein, which would then wake the gene in other [[cell (biology)|cells]].{{citation needed|date=January 2023}}

His second hypothesis forms the basis of the modern prion theory, and proposed that an abnormal form of a cellular protein can convert normal proteins of the same type into its abnormal form, thus leading to replication.{{citation needed|date=January 2023}}

His third hypothesis proposed that the agent could be an [[antibody]] if the antibody was its own target [[antigen]], as such an antibody would result in more and more antibody being produced against itself. However, Griffith acknowledged that this third hypothesis was unlikely to be true due to the lack of a detectable [[immune response]].<ref name="researchgate.net">{{cite book | vauthors = Bolton D | chapter-url = https://www.researchgate.net/publication/235220355 | chapter = Prions, the Protein Hypothesis, and Scientific Revolutions | veditors = Nunnally BK, Krull IS | title = Prions and Mad Cow Disease | publisher = Marcel Dekker | date = January 1, 2004 | pages = 21–60 | via = ResearchGate | isbn = 978-0-203-91297-3 | access-date = July 27, 2018 | archive-date = March 22, 2022 | archive-url = https://web.archive.org/web/20220322123428/https://www.researchgate.net/publication/235220355_Prions_the_Protein_Hypothesis_and_Scientific_Revolutions | url-status = live }}</ref>

[[Francis Crick]] recognized the potential significance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "[[Central dogma of molecular biology]]" (1970): While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith).<ref>{{cite journal | vauthors = Crick F | title = Central dogma of molecular biology | journal = Nature | volume = 227 | issue = 5258 | pages = 561–3 | date = August 1970 | pmid = 4913914 | doi = 10.1038/227561a0 | s2cid = 4164029 | bibcode = 1970Natur.227..561C }}</ref> The revised hypothesis was later formulated, in part, to accommodate [[reverse transcription]] (which both [[Howard Martin Temin|Howard Temin]] and [[David Baltimore]] discovered in 1970).<ref name="pmid27482900">{{cite journal | vauthors = Coffin JM, Fan H | title = The Discovery of Reverse Transcriptase | journal = Annual Review of Virology | volume = 3 | issue = 1 | pages = 29–51 | date = September 2016 | pmid = 27482900 | doi = 10.1146/annurev-virology-110615-035556 | doi-access = free }}</ref>

In 1982, [[Stanley B. Prusiner]] of the [[University of California, San Francisco]], announced that his team had purified the hypothetical infectious protein, which did not appear to be present in healthy hosts, though they did not manage to isolate the protein until two years after Prusiner's announcement.<ref>{{cite journal | vauthors = Taubes G | author-link = Gary Taubes | title =The game of name is fame. But is it science? |journal=Discover |volume=7 |issue=12 |pages= 28–41 |date=December 1986 }}</ref><ref name="Prusiner82">{{cite journal | vauthors = Prusiner SB | title = Novel proteinaceous infectious particles cause scrapie | journal = Science | volume = 216 | issue = 4542 | pages = 136–144 | date = April 1982 | pmid = 6801762 | doi = 10.1126/science.6801762 | url = https://pdfs.semanticscholar.org/f292/b22e2675419c6392a5e55f6b35b1dfc46917.pdf | url-status = dead | s2cid = 7447120 | bibcode = 1982Sci...216..136P | archive-url = https://web.archive.org/web/20200720113942/https://pdfs.semanticscholar.org/f292/b22e2675419c6392a5e55f6b35b1dfc46917.pdf | archive-date = 2020-07-20 }}</ref> The protein was named a prion, for "proteinacious infectious particle", derived from the words protein and infection. When the prion was discovered, Griffith's first hypothesis, that the protein was the product of a normally silent gene, was favored by many. It was subsequently discovered, however, that the same protein exists in normal hosts but in different form.<ref name="pmid26645475">{{cite journal | vauthors = Atkinson CJ, Zhang K, Munn AL, Wiegmans A, Wei MQ | title = Prion protein scrapie and the normal cellular prion protein | journal = Prion | volume = 10 | issue = 1 | pages = 63–82 | date = 2016 | pmid = 26645475 | pmc = 4981215 | doi = 10.1080/19336896.2015.1110293 }}</ref>

Following the discovery of the same protein in different form in uninfected individuals, the specific protein that the prion was composed of was named the prion protein (PrP), and Griffith's second hypothesis, that an abnormal form of a host protein can convert other proteins of the same type into its abnormal form, became the dominant theory.<ref name="researchgate.net"/> Prusiner was awarded the [[Nobel Prize in Physiology or Medicine]] in 1997 for his research into prions.<ref name="nobel">{{cite web | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1997/ | title = The Nobel Prize in Physiology or Medicine, 1997 | access-date = 2010-02-28 | publisher = NobelPrize.org | quote = The Nobel Prize in Physiology or Medicine 1997 was awarded to Stanley B. Prusiner 'for his discovery of Prions - a new biological principle of infection.' | archive-date = 2018-08-09 | archive-url = https://web.archive.org/web/20180809231715/https://www.nobelprize.org/nobel_prizes/medicine/laureates/1997/ | url-status = live }}</ref><ref>{{Cite web| vauthors = Frazer J |title=Prions Are Forever|url=https://blogs.scientificamerican.com/artful-amoeba/prions-are-forever/|access-date=2021-12-28|website=Scientific American Blog Network|language=en|archive-date=2022-01-04|archive-url=https://web.archive.org/web/20220104103748/https://blogs.scientificamerican.com/artful-amoeba/prions-are-forever/|url-status=live}}</ref>