The evolution of drug discovery: from phenotypes to targets, and back†
Cumulative scientific and technological advances over the past two centuries have transformed drug discovery from a largely serendipitous process into the high tech pipelines of today. For thousands of years, medicines were sourced directly from nature, through observing the phenotypic effects of substances on humans or animals. Following the molecular biology revolution and initiation of the human genome project in the 1990s, target-based screening gained popularity and soon came to dominate the pharmaceutical industry. Two decades later, the phenotypic approach began to make a strong comeback, benefiting from the scalability and speed afforded by massive technological advances. This has ignited a debate over the relative productivities of phenotypic and target-based screening. However, as more integrative technologies become available, the focus of the discussion should shift from prioritizing the different approaches to finding strategies that can combine their complementary strengths. This review chronicles major trends and transformative events in the evolution of drug discovery, and underscores the importance of phenotypic approaches for past, and likely future, successes.