Question 3 of 6 Intermediate Scenario
What evidence makes a target biologically and therapeutically credible?
Short answer
Credible targets have convergent evidence linking causal target perturbation to disease benefit, plus a plausible safety and tractability path. Association alone is not enough.
Why
Prioritize human genetic alleles with directional effects where they exist, complemented by disease-relevant tissue and cell data. Test target loss and gain of function with orthogonal perturbations and rescue to uncover causal direction. Evaluate whether dose-dependent modulation produces the intended phenotype without broadly harming cells.
Animal models can be informative, but their relevance to human pathology must be justified rather than assumed. Also assess target accessibility, normal tissue distribution, genetic compensation and likely safety liabilities. For example, a transcript elevated in tumors is an interesting association, while selective genetic depletion that reduces tumor growth and can be rescued by a resistant construct builds stronger causal support.
The therapeutic case remains provisional until intervention and exposure in clinically relevant contexts are demonstrated.
Common mistakes
- Confusing expression correlation, pathway enrichment or a single knockout phenotype with therapeutic validation
The interviewer might ask next
What would make strong genetic evidence fail to translate into a useful drug target?