In preclinical drug development, choosing the right biological model is the most critical initial decision. Selecting an inappropriate model, such as the wrong PDX or organoid line, guarantees the research program will fail as it will be designed to answer the wrong question from the outset.

The push away from animal models is a technical necessity, not just an ethical one. Advanced therapeutics like T-cell engagers and multispecific antibodies depend on human-specific biological pathways. These mechanisms are not accurately reproduced in animal models, rendering them ineffective for testing these new drug classes.

The most valuable lessons in clinical trial design come from understanding what went wrong. By analyzing the protocols of failed studies, researchers can identify hidden biases, flawed methodologies, and uncontrolled variables, learning precisely what to avoid in their own work.

Only 5% of investigational cancer drugs reach the market due to the gap between lab models and human biology. Dr. Saav Solanki highlights organoids, which use real patient tissue, as a key translational model to improve the predictive accuracy of preclinical research and increase the low success rate.

The danger of LLMs in research extends beyond simple hallucinations. Because they reference scientific literature—up to 50% of which may be irreproducible in life sciences—they can confidently present and build upon flawed or falsified data, creating a false sense of validity and amplifying the reproducibility crisis.

The gap between benchmark scores and real-world performance suggests labs achieve high scores by distilling superior models or training for specific evals. This makes benchmarks a poor proxy for genuine capability, a skepticism that should be applied to all new model releases.

The traditional method of engineering enzymes by making precise, knowledge-based changes (“rational design”) is largely ineffective. Publication bias hides the vast number of failures, creating a false impression of success while cruder, high-volume methods like directed evolution prove superior.

Unlike using genetically identical mice, Gordian tests therapies in large, genetically varied animals. This variation mimics human patient diversity, helping identify drugs that are effective across different biological profiles and addressing patient heterogeneity, a primary cause of clinical trial failure.

The temptation is to use the most advanced technology available. A more effective approach is to first define the specific biological question and then select the simplest possible model that can answer it, thus avoiding premature and unnecessary over-engineering.