In Vivo vs In Vitro: Advantages of Zebrafish Models

The drug discovery process is a lengthy and expensive endeavor that can take up to a decade or more and cost upwards of $1 billion. In order to develop effective drugs, researchers use preclinical trials to identify specific molecules (Lead Candidates) that possess the necessary characteristics. During this preclinical stage, both in vivo and in vitro assays are used to validate targets and the development of candidates.

In vitro (Latin for “in glass”) refers to studies done externally of a living organism. This can include work done on bacteria or mammal cells in a petri dish. In vitro pre-clinical tests are useful for identifying any toxic or carcinogenic reactions. For example, a 2017 study on potential cancer treatments used in vitro tumor cells and high throughput drug screening to validate a personalized cancer drug. Tests results identified an effective new drug and drug combinations created for each specific cell. Tissue chips are another exciting and emerging in vitro technology that uses engineered microsystems to represent human organ tissues.

In vivo (“within the living”) involves research conducted within the body of a living model. Around 30% of drugs that have passed in vitro pre-clinical studies fail clinical trials, so performing in vivo assays is an essential step in the drug discovery process as it reveals drug effects on whole, complex organisms. In vivo models have the distinct advantage of testing toxicity, efficacy, and safety of a drug based on a whole, complex, living organism. Gene editing in animals has made these processes even more successful.

Both in vivo and in vitro methods have their place in the world of research and are often used to complement each other. Depending on the application, there are advantages and disadvantages. In vitro research holds the advantages of being less expensive and therefore more suitable for high throughput, large scale pharmaceutical testing. From an ethical standpoint, in vitro is also favored and does not require approval from Institutional Animal Care and Use Committees (IACUCs). A significant drawback is that in vitro fails to address the complexity of organ systems. Biochemical processes like metabolization are not accounted for and therefore they are not as ‘translatable’ to humans.

In vivo studies are more costly (in terms of time and resources) and raise ethical concerns from many entities. However, in vivo models have the distinct advantage of testing toxicity, efficacy, and safety of a drug based on a whole, complex, living organism. Gene editing in animals has made these processes even more successful.

Source: NCBI

Zebrafish: Alternative model

Zebrafish have a unique set of advantages in drug discovery and development. They are often seen as a bridge between in vitro and in vivo models. From a resource standpoint, zebrafish are much more cost-effective in terms of housing, maintaining, and breeding when compared to mice. They are also extremely adaptable to varying conditions. Zebrafish embryos are transparent, and are fertilized and developed externally, allowing scientists to manipulate and observe drugs´ effects directly using image analysis techniques which are very suitable for phenotypic screenings.

The 2010 European Commission Directive states that experiments with some early life-stage animals, such as zebrafish, are not considered experimental animals until they exit the chorion and start feeding independently. This means research using zebrafish embryos under five to six days post-fertilization (dpf) are not considered experimental animals, but are alternative animal models. Therefore, zebrafish are under the 3Rs Principle: Replacement, Reduction, and Refinement of animals, which aim to increase animal welfare in research without reducing scientific advances.

In conclusion, in vivo vs in vitro studies have their place in early drug discovery processes. Zebrafish as a model offer distinct advantages and provide an affordable, effective, and more ethical option when animal testing is necessary, combining advantages from both in vitro and in vivo.


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