Editing Serial passage (section)

==Experiments==
Researchers have conducted many experiments using serial passage.  Some of the experimental uses for serial passage include changing the virulence of a virus, to study the adaptive evolution or potential evolution of [[zoonotic diseases]] to new hosts, and studying [[antibiotic resistance]].

===Increasing virulence for use in animal modeling===
When developing vaccines for viruses, the emphasis is on attenuating the virus, or decreasing its virulence, in a given host.  Sometimes it is useful to employ serial passage to increase the virulence of a virus.  Usually, when serial passage is performed in a species, the result is a virus that is more virulent to that species.<ref name = woo/>

For example, one study<ref name="locher">{{Cite journal |vauthors=Locher CP, Witt SA, Herndier BG, Abbey NW, Tenner-Racz K, Racz P, Kiviat NB, Murthy KK, Brasky K, Leland M, Levy JA |date=January 2003 |title=Increased virus replication and virulence after serial passage of human immunodeficiency virus type 2 in baboons |journal=Journal of Virology |volume=77 |issue=1 |pages=77–83 |doi=10.1128/jvi.77.1.77-83.2003 |pmc=140565 |pmid=12477812}}</ref> used serial passage in baboons to create a strain of HIV-2 that is particularly virulent to baboons.  Typical strains of HIV-2 only infect baboons slowly.<ref name=locher/>  This specificity makes it challenging for scientists to use HIV-2 in animal models of HIV-1, because the animals in the model will only show symptoms slowly. The more virulent strain of HIV-2 could be practical for use in animal models, however.<ref name=locher/>

Another study by Kanta Subbaro involved a serial passage experiment in which mice were infected with [[SARS]].<ref name="zimmer">{{Cite book |last=Zimmer |first=Carl |title=The Tangled Bank |date=2013 |publisher=Robert and Co. Publishers |edition=second |pages=399–427 |chapter=Chapter 15}}</ref>  SARS usually does not make mice particularly sick, however, after the virus had undergone serial passage in the mice, it had become lethal.<ref name="zimmer" />

Changing the virulence of SARS in this way was important, because without a virulent form of SARS to infect laboratory animals, scientists would have been unable to test the effects of SARS in an animal model.<ref name="zimmer" />

More generally, this experiment also reflects a general medical principle: The virulence of a virus is mediated by the difficulty of its transmission.

Generally, if a virus kills its host too quickly, the host will not have a chance to come in contact with other hosts and transmit the virus before dying.  In serial passage, when a virus was being transmitted from host to host regardless of its virulence, such as Subbaro's experiment, the viruses that grow the fastest (and are therefore the most virulent) are selected for.<ref name="zimmer" />

This principle has public health implications, because it suggests that, in very densely populated or overcrowded areas, such as slums or [[Pest house|group quarantine facilities]], natural selection may favour more virulent viruses.

This also helps explain why good hygiene is so important. Good hygiene selects against highly virulent viruses by lowering the ability of pathogens to transmit.<ref name="zimmer" />

Serial passaging has been used to produce mouse-adapted SARS-CoV-2.<ref name="pandey">{{Cite journal |last1=Pandey |first1=Kabita |last2=Acharya |first2=Arpan |year=2021 |title=Animal models for SARS-CoV-2 research: A comprehensive literature review |journal=Transboundary and Emerging Diseases |publication-date=October 2020 |volume=68 |issue=4 |pages=1868–1885 |doi=10.1111/tbed.13907 |pmc=8085186 |pmid=33128861}}</ref><ref>{{cite journal|vauthors=Gu H, Chen Q, Yang G, He L, Fan H, Deng YQ, Wang Y, Teng Y, Zhao Z, Cui Y, Li Y, Li XF, Li J, Zhang NN, Yang X, Chen S, Guo Y, Zhao G, Wang X, Luo DY, Wang H, Yang X, Li Y, Han G, He Y, Zhou X, Geng S, Sheng X, Jiang S, Sun S, Qin CF, Zhou Y|title=Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy|journal=Science|volume=369|issue=6511|pages=1603–1607|date=25 September 2020|pmid=32732280|pmc=7574913|doi=10.1126/science.abc4730}}</ref>

===Influenza===
The [[H5N1]] virus is a particularly lethal strain of [[influenza]]. Currently, it can infect humans, but it is not [[contagious disease|contagious]] between humans. Still, over 600 people worldwide are known to have died from animal-transmitted H5N1 virus,<ref name="zimmer" /> so the transmissibility of the virus is of major concern to scientists.

Several serial passage experiments have been conducted to determine the feasibility of the virus becoming transmissible in humans. In particular, Ron Fouchier and his colleagues did a 10-step serial passage experiment in ferrets.<ref name="zimmer" /> In doing so, they created a strain of influenza that not only infected ferrets, but was transmissible between ferrets.<ref name="zimmer" /> Notably, this strain was very similar to the original strain with which they had infected the first ferret—in other words, only a few mutations were necessary for the virus to become transmissible between ferrets.<ref name="zimmer" /><ref name="puiu">{{Cite web |date=3 May 2012 |title=H5N1 controversial paper shows that bird flu is only a genetic mutation away from mammal flu. |url=http://www.zmescience.com/research/h5n1-bird-flu-paper-genetic-mutation-human-transmission-05032/ |access-date=26 April 2014 |website=ZME Science |vauthors=Puiu T}}</ref>  Similarly, researcher Yoshihiro Kawaoka found that a single mutation is necessary to make the virus transmissible in ferrets.<ref name="puiu" />

Both Fouchier's research and Kawaoka's research were initially censored, per implications for [[bioterrorism]].<ref name="puiu" /> The research was later published, but remained controversial.<ref name="puiu" />

Serial passage is an artificial technique that is used in a laboratory setting, rather than a natural process.  Accordingly, the likelihood that the H5N1 virus would actually mutate to become transmissible in humans is unknown; however, researcher Derek Smith created an evolutionary model to show that this is possible.<ref name="zimmer" />

===Understanding how viruses jump between species===
Another use of serial passage is in understanding how pathogens adapt to new species.  By introducing a pathogen into a new host species and performing serial passage, scientists can observe as the pathogen adapts to its new host and pinpoint the mutations that allow for this adaptation.<ref name="woo" />