For the past three decades, the use of genomics to inform drug discovery and development pipelines has generated both excitement and scepticism. Although earlier efforts successfully identified some new drug targets, the overall clinical efficacy of developed drugs has remained unimpressive, owing in large part to the heterogeneous causes of disease. Recent technological and analytical advances in genomics, however, have now made it possible to rapidly identify and interpret the genetic variation underlying a single patient's disease, thereby providing a window into patient-specific mechanisms that cause or contribute to disease, which could ultimately enable the 'precise' targeting of these mechanisms. Here, we first examine and highlight the successes and limitations of the earlier phases of genomics in drug discovery and development. We then review the current major efforts in precision medicine and discuss the potential broader utility of mechanistically guided treatments going forward.

在过去的三十年中，利用基因组学为药物发现和开发流程提供信息既引起了兴奋，也引起了怀疑。尽管早期的努力成功地确定了一些新的药物靶点，但已开发药物的总体临床疗效仍然不理想，这在很大程度上归因于疾病的异质性原因。然而，基因组学的最新技术和分析进展现在使得快速识别和解释单个患者疾病背后的遗传变异成为可能，从而为了解导致或促成疾病的患者特异性机制提供了一个窗口，这最终可能使“精确”瞄准这些机制。在这里，我们首先检查并强调基因组学早期阶段在药物发现和开发方面的成功和局限性。然后，我们回顾了当前在精准医学方面的主要努力，并讨论了机械引导治疗未来潜在的更广泛的用途。