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Using Zebrafish in Human Disease Research: Some Advantages, Disadvantages and Ethical Considerations

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Using Zebrafish in Human Disease Research: Some Advantages, Disadvantages and Ethical Considerations Using zebrafish in human disease research: some advantages, disadvantages and ethical considerations Dr Michael Lardelli spacecraft (Dubinin et al. 1977) where weightlessness Discipline of Genetics was seen to have no deleterious effects. School of Molecular and Biomedical Science Zebrafish embryos can hatch after 48 hours of The University of Adelaide development. At 24 hours their overall body plan has Adelaide, SA 5005, Australia been laid out and the primordia of many organ sys- tems are in place (Thisse & Zon 2002). Thus, embryos of the vertebrate zebrafish develop at a rate similar to Introduction the rapidly developing embryos of the insect model organism, Drosophila melanogaster. Like Drosophila (and The zebrafish, Danio rerio, is a small teleost fish origi- in contrast to the mouse) the embryos of zebrafish nating from the rivers of northern and eastern India develop predominantly by cell division without exten- (Engeszer et al. 2007). It possesses a number of advan- sive growth. This means that early embryos are large tageous physical characteristics that have resulted in enough to manipulate easily (e.g., inject with sub- its common use today as a laboratory model. These stances to regulate gene expression) but they remain include its relatively small adult size of 2–3 cm, its small enough during development to allow the use rapid generation time of approximately 3 months, its of particular analytical techniques. For example, the ability to produce large clutches of externally fertil- technique of “whole mount in situ transcript hybridi- ised eggs and the ease with which this fish can be kept sation”, in which cells in whole embryos are stained and bred in aquaria. if they transcribe a particular gene (Jowett & Lettice The development of zebrafish as a genetic model 1994), can be used throughout zebrafish embryogen- began with the work of George Streisinger in the esis but only up until day 11 of the 20 days of mouse 1960s (reviewed in Grunwald & Eisen 2002). Stre- embryogenesis. The external fertilisation of zebrafish issinger developed a number of techniques to manip- eggs means that it is possible to observe the normal or ulate the ploidy of zebrafish eggs and zygotes and abnormal development of living zebrafish embryos. was ultimately able to use these techniques to produce This is not generally possible with mice where obser- homozygous, genetically identical individuals (clones) vation of embryo development usually requires sacri- (Streisinger et al. 1981). Streisinger and his cowork- fice of the mother and death of the embryo. Impor- ers also established techniques for forward genetic tantly, mouse embryos that die during development screening in zebrafish (Walker & Streisinger 1983; are rapidly broken down and reabsorbed whereas Grunwald et al. 1988). dead zebrafish embryos tend to persist for a while in The transparent embryos of zebrafish develop their final state. synchronously and extremely rapidly. Published stud- With Streisinger’s work as a foundation, Chris- ies examining the development of zebrafish embryos tiane Nüsslein-Volhard and Wolfgang Driever con- can be found as early as 1952 (Battle & Hisaoka ducted independent, large-scale forward genetic 1952). Zebrafish embryo development has even been screens for mutations affecting embryo development. examined in orbit aboard the Soyuz 19 (and other) The descriptions of the mutant phenotypes they TRANSGENICS AND MODELLING 23 discovered were published in a single issue of the The ability to perform large-scale random mutagen- journal Development in 1986 (volume 123). While muta- esis screens in zebrafish allows objective investigation tions affecting the development of vertebrates had of control biological processes that are not hamstrung previously been identified (e.g., in mice early in the by a researcher’s preconceptions of how a process 20th Century in inbred strains and in radiation muta- might function. When zebrafish models of human genesis screens in the 1950s, Lyon 2002) no large- genetic diseases are available the ability to screen for scale screens had previously been attempted. The modifier mutations (that suppress or enhance the dis- results of the large scale zebrafish mutation screens ease phenotype) using zebrafish allows dissection of led to the establishment of a number of models of the biological processes underlying the disease. human genetic disease (reviewed by Lieschke & Cur- rie 2007). Manipulation of gene activity The technology for manipulation of zebrafish gene Advantages of work with zebrafish activity is less sophisticated than that available for the mouse but, nevertheless, quite extensive. While The current and growing popularity of using zebrafish targeted mutagenesis (“knock-out”) or gene replace- for research into human disease can be attributed to ment (“knock-in”) by homologous recombination is its favourable physical characteristics, ready experi- not practical, very high rates of random mutagenesis mental manipulation and the extensive knowledge can be achieved using chemical mutagens such as base on this organism that now exists. The low rela- N-ethyl-N-nitrosourea (ENU) (Grunwald & Streis- tive cost of maintaining a zebrafish facility compared inger 1992). It is possible to screen for mutations in to mice is also important. any particular gene when these are in a heterozygous state in the progeny of fish exposed to ENU. Iso- Zebrafish genetics lated mutations can then be bred to homozygosity. Zebrafish are vertebrates and so share a closer struc- This process, known as TILLING (Targeted Induced tural and physiological relationship to humans than Local Lesions in Genomes) is now in common use in invertebrate models. The zebrafish and human lin- zebrafish (Wienholds et al. 2003). Recently, a method eages diverged approximately 450 million years ago of inducing small deletions in targetted genes has (Kumar & Hedges 1998) and their genomes are of been developed that relies on creation of proteins similar size. Orthologues of most human genes can that can bind specifically to the desired gene and then be found in zebrafish and these commonly show cause cleavage of the DNA (Doyon et al. 2008; Meng similar patterns of expression. Orthologous proteins et al. 2008). are commonly approximately 70% identical in terms of their amino acid residue sequence. Interestingly, a Transgenics widespread gene duplication event appears to have Considerable work has been done to develop trans- occurred in the zebrafish lineage such that duplicate genic technologies for the zebrafish (reviewed by orthologues of some zebrafish genes exist (reviewed Amsterdam & Becker 2005). In particular, the trans- by Postlethwait 2007). Frequently, the functions of a posons Sleeping Beauty (reconstructed from genomic single human gene are found to be divided between “fossil” evidence, Davidson et al. 2003) and Tol2 the two zebrafish orthologues (i.e. “subfunctionalisa- from the fish Oryzias latipes (common name medaka, tion” has occurred, Lynch & Force 2000). This can be Kawakami 2007) can be used both as vectors for advantageous when loss of function of only one of transgenesis as well as for insertional mutagenesis. the two zebrafish genes produces a simpler pheno- Transgenesis is also possible either through injection type that is more amenable to analysis than the human into fertilised oocytes of naked DNA fragments or disease phenotype. If needed, it is also possible to DNA coinjected with I-SceI endonuclease (Grabher et abolish simultaneously the function of both zebrafish al. 2004). Conditional expression of genes is possible genes, at least during embryo development, by injec- either through use of heat shock promoters (Shoji & tion of antisense morpholino oligonucleotides (see Sato-Maeda 2008) or the Gal4/UAS system (Asakawa below). & Kawakami 2008). In general, reliable expression of 24 BLUE SKY TO DEEP WATER: THE REALITY AND THE PROMISE transgenes is obtained in zebrafish only when fish, not was fused to the fluorescent protein coding gene mammalian, promoters are used. mCherry to create a fusion protein that marked β cells Both transient and stable transgenesis of zebrafish before ablation without affecting nitroreductase activ- can be used to create models of human disease ity (Pisharath et al. 2007). states. In particular, this has allowed construction of zebrafish cancer models (e.g., Onnebo et al. 2005; Morpholino antisense oligonucleotides Chen et al. 2007). Human cancer cells have been suc- Morpholino oligonucleotides are polymers of nucleic cessfully grafted into zebrafish embryos where their acid bases attached to morpholine rings (rather than ability to reorganise surrounding tissues and their deoxyribose rings) linked through phosphorodiami- sensitivity to anti-cancer treatments can be assessed date groups (Summerton & Weller 1997). They are (Geiger et al. 2008; Stoletov & Klemke 2008). The highly resistant to degradation by cellular nucle- recent generation of mutant zebrafish that are com- ases. Antisense morpholino oligonucleotides can be pletely transparent (i.e. do not develop pigment cells) designed that can bind to complementary sequences will assist analysis of tumour formation and treatment in gene transcripts before splicing (to inhibit splicing) (White et al. 2008). or in mRNA (to inhibit translation). When injected into newly fertilised zebrafish eggs they can effec- Ease of drug treatment tively and specifically suppress mRNA translation for Much of the enthusiasm for modelling of human at least two days of development
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