Typical reductionist approach – iPSCs in disease modelling 1) finding out how much a particular

iPSCs in disease modelling

1) finding out how much a particular variant/mutation contributes to the phenotype (correcting or

inducing genetic polymorphisms)

2) alternatively, using reporter genes to discover which genes are essential for cell differentiation,

and in knockout mouse models, how cell differentiation is different/impacted (e.g. dopaminergic

neuron development in Parkinson’s)

3) after differentiation, these cells can undergo function and neurotoxicity assays for further

study of disease phenotype create organoid structures to study cell interactions and removes the

effect of complex tissue environment on cell physiology

Typical reductionist approach

1) Early Stages of Drug Development:

High Throughput Screening (HTS): In the early stages, drug candidates are often evaluated through high

throughput screening (HTS) using in vitro assays. These assays involve testing a large number of

chemical compounds from libraries to identify potential candidates that exhibit some desired activity.

(Test drug candidates via HTS using in vitro library assays — > try to identify potential candidates that

exhibit desired activity)

Simple Cell Culture Systems: Researchers might also use simple cell culture systems. These systems

often involve cells that are dividing and do not have a mature phenotype. Additionally, they may

overexpress a specific target protein. While these cell culture systems allow for testing compounds in a

controlled environment, they are relatively simple and may not represent the complexity of tissues or

organs in the human body. They are mainly used to identify potential hits or leads for further

development.

(Simple cell cultures are used meaning these cells are dividing actively and do not have mature

phenotype. Additionally, they may overexpress a specific target protein. While these cell culture systems

allow for testing compounds in controlled environment, they are relatively simple and may not represent

the complexity of tissue or organs in human body)

Limitations: The assays used in these early stages of drug discovery are often reductionist, meaning they

simplify biological systems for the sake of efficiency and throughput. As a result, they may not fully

reflect the function of a compound in the context of the tissue or organ of interest. The assays focus on

basic interactions without necessarily capturing the broader biological function.

Clinical Selection of the Drug:

Tissue Assays: In the later stages of drug development, traditional tissue pharmacological assays may be

used. These assays involve testing the drug candidate on actual tissues relevant to the therapeutic target.

However, these assays are often low throughput, meaning they can only be used to test a relatively small