构建可预测并解释细胞对药物反应的虚拟细胞,助力高效安全的新药发现。
Virtual Cells: Predict, Explain, Discover
- 用AI建模细胞对各种药物扰动的功能响应,模拟真实生物机制。
- 需能准确预测响应并解释关键分子互作变化导致的结果。
- 适合新药研发人员、计算生物学与系统药理学研究者使用。
药物发现本质上是推断治疗对患者影响的过程,若能有可靠的计算模型模拟患者反应,将极大提升研究效率,使研究人员在昂贵临床试验前安全、经济地生成和测试大量治疗假说。即使仅能预测细胞对广泛扰动的功能响应,也极具价值,有助于发现安全有效的疗法并成功转化至临床。尽管构建此类虚拟细胞长期是计算研究领域的目标,但因细胞生物学的复杂性和规模,至今未实现。然而,人工智能、算力、实验室自动化及高通量细胞分析技术的进步,为实现这一目标带来了新机遇。本文基于我们在Recursion的经验,提出虚拟细胞的发展与评估愿景:要成为发现新生物学的有效工具,虚拟细胞必须准确预测细胞对扰动的响应,并解释该响应如何源于关键生物分子互作的改变。我们提出设计治疗相关虚拟细胞的核心原则,描述了“实验室闭环”方法以从中获得新见解,并倡导基于生物学的基准来指导开发。最后,我们主张该方法可推广至更高组织层次的模型,如虚拟患者。我们希望这些方向能为研究社区提供有益参考,推动面向药物发现成果优化的虚拟模型发展。
原文摘要 · Abstract (English)
Drug discovery is fundamentally a process of inferring the effects of treatments on patients, and would therefore benefit immensely from computational models that can reliably simulate patient responses, enabling researchers to generate and test large numbers of therapeutic hypotheses safely and economically before initiating costly clinical trials. Even a more specific model that predicts the functional response of cells to a wide range of perturbations would be tremendously valuable for discovering safe and effective treatments that successfully translate to the clinic. Creating such virtual cells has long been a goal of the computational research community that unfortunately remains unachieved given the daunting complexity and scale of cellular biology. Nevertheless, recent advances in AI, computing power, lab automation, and high-throughput cellular profiling provide new opportunities for reaching this goal. In this perspective, we present a vision for developing and evaluating virtual cells that builds on our experience at Recursion. We argue that in order to be a useful tool to discover novel biology, virtual cells must accurately predict the functional response of a cell to perturbations and explain how the predicted response is a consequence of modifications to key biomolecular interactions. We then introduce key principles for designing therapeutically-relevant virtual cells, describe a lab-in-the-loop approach for generating novel insights with them, and advocate for biologically-grounded benchmarks to guide virtual cell development. Finally, we make the case that our approach to virtual cells provides a useful framework for building other models at higher levels of organization, including virtual patients. We hope that these directions prove useful to the research community in developing virtual models optimized for positive impact on drug discovery outcomes.
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