The Drug Discovery process involves multiple steps, and every stage needs to meet highly strict standards and regulations. Before a new molecule or potential treatment can move forward to clinical trials, everything about its toxicity, safety, and efficacy needs to first be researched in preclinical studies.
Finding a preclinical model that is highly homologous to humans ensures all the tests and assays produce relevant and reliable data. Choosing the right preclinical model depends on the scope and scale of the study, but always needs to provide relevant results that highlight any potential harmful effects. There are many options for experimental models, ranging from the classic white mice to alternative models like synthetic organs and vertebrate fish.
In this article we will review possible preclinical models, including six alternative models, to help make it easier to find an option for early stages Drug Discovery.
Mammal models usually fall under the category of a few rodent species, although it can include more. The iconic white mouse is so commonly associated with laboratories and medical research, but it's worth mentioning how important they have been to biomedical science. That strong connection to research is rooted in a long history of using mice and rats as preclinical models.
The small mammals have a lot in common with humans, sharing around 90% of the human genome and, importantly, mammalian biological structures. While rodents have helped progress modern medicine over the last century, there is growing concern around their continual use.
The 3Rs (Replacement, Reduction and Refinement) have been widely adopted as increasing regulations and higher ethical standards push for a decrease in the use of mammals in research.
Zebrafish are an alternative animal model for preclinical studies that has grown in popularity over the past few decades. The small fish fill a unique niche, sharing similar genetic structures to humans while also being cost effective and exhibiting natural behaviors. All together, this model leads to more ethical research.
Zebrafish are a valuable alternative preclinical model for in vivo testing in Drug Discovery. With development taking less than a week and laying hundreds of transparent eggs, Zebrafish have been quickly picked up by scientists and researchers looking to move towards clinical trials. As an established alternative, they have already played an important role in the discovery of cancer treatments, heart and CNS diseases, toxicity, and much more.
Daphnia are a freshwater crustacean that is a cost effective option for studies on aquatic toxicity. Thousands of the aquatic invertebrates can be cultured in a lab at once, making them an ideal choice for toxicity assays that need to be performed at a large scale.
Their short lifespan (10-30 days), transparent membranes, and high sensitivity to chemicals make them easily adaptable to the quick pace of early Drug Discovery. With their internal organs clearly visible, scientists can directly observe how changes to an environment affect the organism.
Daphnia are highly sensitive to chemicals, displaying clear and obvious signals with changes in temperatures, altered feeding patterns, and reductions in oxygen.
4. In Vitro Cell Cultures
Cell culture involves growing cells and continuous cell lines outside of their natural environment and under controlled laboratory conditions. The most basic form of cell cultures are found in small samples kept on flat plastic dishes and assayed on multi-well plates. This in vitro two-dimensional structure provides basic information about cell biology and drug activity with minimal time and attention.
More advanced forms of cell cultures grow on three-dimensional structures that more accurately mimic in vivo cell interactions. The most advanced cell structures add another dimension to the model, allowing for observations on how cells change over a period of time.
5. Organs on a Chip
Organs on a chip are a type of artificial organ that simulates real human tissues with biomedically-engineered in vivo recreations. The cutting edge technology and impressive engineering of organs on a chip shows a lot of promise for future preclinical models but the practical application of microfluidic cultures remains in its infancy.
These advances bring new challenges and opportunities but there is some concern around the incomplete information derived from studying isolated organs outside of their biological context. In practice, that means that currently there is still a need for alternative animal models that provide a more complete picture of the toxicity, safety and efficacy of a new treatment.
6. Human Based Cell Models
Preclinical models derived from human stem cells and other human cell-based in vitro systems are grouped under human based cell models. These specific models help researchers screen for potential new drugs and provide data on harmful side effects.
The highly precise models are based on real human cells while keeping experiments in vitro. These human based cell models are based on functional cell types such as cardiomyocytes, hepatocytes or neurons that have been fully differentiated from human induced pluripotent stem cells (iPSCs). This unique blend of relevant data and practicality has shown significant success in determining several functional and safety assays including skin irritation, pyrogenicity, organ toxicity, and modular immunity.
Bright Future for Alternative Preclinical Models
The increased concern around the use of mammals in research has led to more interest in alternative models. The 3Rs are now widely adopted as government regulations, becoming the industry standard for much of the scientific community.
Reducing and eliminating animal testing includes completely synthetic options, in vitro models, and computer approaches, but there is still a need for testing on living organisms.
Alternative animal models like Zebrafish and daphnia fill the gap between completely synthetic approaches and mammal models. The right choice for a new hit ready to enter preclinical studies will always depend on what exactly needs to be tested.
Zebrafish in particular are a great example of an alternative model that is cost effective while still being highly homologous to humans. There are advantages and disadvantages to every option, but Zebrafish offer a nice middle ground, giving researchers access to the benefits associated with mammals in a more ethical and scalable package.