Editing Zebrafish (section)

==Drug discovery and development==
[[File:Zebrafish Make a Splash in FDA Research (8614532586).jpg|thumb|FDA research used Zebrafish to show the effects of [[ketamine]] on neurological development.]]
The zebrafish and zebrafish larva is a suitable model organism for drug discovery and development. As a vertebrate with 70% genetic homology with humans,<ref name=howe2013/> it can be predictive of human health and disease, while its small size and fast development facilitates experiments on a larger and quicker scale than with more traditional [[Animal testing|in vivo]] studies, including the development of higher-throughput, automated investigative tools.<ref>{{cite journal |vauthors=Martin WK, Tennant AH, Conolly RB, Prince K, Stevens JS, DeMarini DM, Martin BL, Thompson LC, Gilmour MI, Cascio WE, Hays MD, Hazari MS, Padilla S, Farraj AK |display-authors=6 |title=High-Throughput Video Processing of Heart Rate Responses in Multiple Wild-type Embryonic Zebrafish per Imaging Field |journal=[[Scientific Reports]] |volume=9 |issue=1 |page=145 |date=January 2019 |pmid=30644404 |pmc=6333808 |doi=10.1038/s41598-018-35949-5 |bibcode=2019NatSR...9..145M}}</ref><ref>{{cite journal |vauthors=Teixidó E, Kießling TR, Krupp E, Quevedo C, Muriana A, Scholz S |title=Automated Morphological Feature Assessment for Zebrafish Embryo Developmental Toxicity Screens |journal=Toxicological Sciences |volume=167 |issue=2 |pages=438–449 |date=February 2019 |pmid=30295906 |pmc=6358258 |doi=10.1093/toxsci/kfy250}}</ref> As demonstrated through ongoing research programmes, the zebrafish model enables researchers not only to identify genes that might underlie human disease, but also to develop novel therapeutic agents in drug discovery programmes.<ref>{{cite web |url=http://www.fishforscience.com/ |title=Fish for Science |publisher=University of Sheffield |year=2011 |access-date=March 19, 2011 |archive-date=November 12, 2020 |archive-url=https://web.archive.org/web/20201112013436/https://fishforscience.com/ |url-status=live}}</ref> Zebrafish embryos have proven to be a rapid, cost-efficient, and reliable [[Teratogen|teratology]] assay model.<ref>{{cite journal |vauthors=Brannen KC, Panzica-Kelly JM, Danberry TL, Augustine-Rauch KA |title=Development of a zebrafish embryo teratogenicity assay and quantitative prediction model |journal=Birth Defects Research Part B: Developmental and Reproductive Toxicology |volume=89 |issue=1 |pages=66–77 |date=February 2010 |pmid=20166227 |doi=10.1002/bdrb.20223}}</ref>

===Drug screens===
Drug screens in zebrafish can be used to identify novel classes of compounds with biological effects, or to repurpose existing drugs for novel uses; an example of the latter would be a screen which found that a commonly used statin ([[rosuvastatin]]) can suppress the growth of [[prostate cancer]].<ref>{{cite journal |vauthors=Rennekamp AJ, Peterson RT |title=15 years of zebrafish chemical screening |journal=Current Opinion in Chemical Biology |volume=24 |pages=58–70 |date=February 2015 |pmid=25461724 |pmc=4339096 |doi=10.1016/j.cbpa.2014.10.025}}</ref> To date, 65 small-molecule screens have been carried out and at least one has led to clinical trials.<ref name=":0">{{cite journal |vauthors=MacRae CA, Peterson RT |title=Zebrafish as tools for drug discovery |journal=[[Nature Reviews Drug Discovery]] |volume=14 |issue=10 |pages=721–731 |date=October 2015 |pmid=26361349 |doi=10.1038/nrd4627 |s2cid=1979653}}</ref> Within these screens, many technical challenges remain to be resolved, including differing rates of drug absorption resulting in levels of internal exposure that cannot be extrapolated from the water concentration, and high levels of natural variation between individual animals.<ref name=":0" />

===Toxico- or pharmacokinetics===
To understand drug effects, the internal drug exposure is essential, as this drives the pharmacological effect. Translating experimental results from zebrafish to higher vertebrates (like humans) requires concentration-effect relationships, which can be derived from [[pharmacokinetic]] and [[pharmacodynamic]] analysis.<ref name = vanwijk2016>{{Cite journal |last1=Van Wijk |first1=Rob C |last2=Krekels |first2=Elke HJ |last3=Hankemeier |first3=Thomas |last4=Spaink |first4=Herman P |last5=Van der Graaf |first5=Piet H |name-list-style=vanc |title=Systems pharmacology of hepatic metabolism in zebrafish larvae |journal=Drug Discovery Today: Disease Models |doi=10.1016/j.ddmod.2017.04.003 |year=2017 |volume=22 |pages=27–34 |doi-access=free |hdl=1887/49224 |hdl-access=free}}</ref>
Because of its small size, however, it is very challenging to quantify the internal drug exposure. Traditionally multiple blood samples would be drawn to characterize the drug concentration profile over time, but this technique remains to be developed. To date, only a single pharmacokinetic model for [[paracetamol]] has been developed in zebrafish larvae.<ref name=kantae2016>{{cite journal |vauthors=Kantae V, Krekels EH, Ordas A, González O, van Wijk RC, Harms AC, Racz PI, van der Graaf PH, Spaink HP, Hankemeier T |display-authors=6 |title=Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude |journal=Zebrafish |volume=13 |issue=6 |pages=504–510 |date=December 2016 |pmid=27632065 |pmc=5124745 |doi=10.1089/zeb.2016.1313}}</ref>

===Computational data analysis===
Using smart data analysis methods, pathophysiological and pharmacological processes can be understood and subsequently translated to higher vertebrates, including humans.<ref name = vanwijk2016/><ref name = schulthess2018>{{cite journal |vauthors=Schulthess P, van Wijk RC, Krekels EH, Yates JW, Spaink HP, van der Graaf PH |title=Outside-In Systems Pharmacology Combines Innovative Computational Methods With High-Throughput Whole Vertebrate Studies |journal=CPT: Pharmacometrics & Systems Pharmacology |volume=7 |issue=5 |pages=285–287 |date=May 2018 |pmid=29693322 |pmc=5980533 |doi=10.1002/psp4.12297 |name-list-style=vanc}}</ref> An example is the use of [[systems pharmacology]], which is the integration of [[systems biology]] and [[pharmacometrics]]. 
Systems biology characterizes (part of) an organism by a mathematical description of all relevant processes. These can be for example different signal transduction pathways that upon a specific signal lead to a certain response. By quantifying these processes, their behaviour in healthy and diseased situation can be understood and predicted. 
Pharmacometrics uses data from preclinical experiments and [[clinical trials]] to characterize the pharmacological processes that are underlying the relation between the drug dose and its response or clinical outcome. These can be for example the drug [[absorption (pharmacology)|absorption]] in or [[clearance (pharmacology)|clearance]] from the body, or its interaction with the target to achieve a certain effect. By quantifying these processes, their behaviour after different doses or in different patients can be understood and predicted to new doses or patients.
By integrating these two fields, systems pharmacology has the potential to improve the understanding of the interaction of the drug with the biological system by mathematical quantification and subsequent prediction to new situations, like new drugs or new organisms or patients.
Using these computational methods, the previously mentioned analysis of paracetamol internal exposure in zebrafish larvae showed reasonable correlation between paracetamol clearance in zebrafish with that of higher vertebrates, including humans.<ref name=kantae2016/>