Evolution and optimization of synthetic <READ/WRITE> function from and into cells using genetic programming

机器学习和人工智能的巨大进步改变了许多方面 我们生活中的一部分。人工智能融入生物医学领域，让我们能够解决复杂的生物 这些问题是发展进步的诊断和治疗工具的瓶颈。一个例子是 需要操纵肽的氨基酸序列以提高其作为生物活性分子的功能。 在这些新技术的基础上，我们开发了一种基于某一学科的新机器学习工具 这被称为“基因编程”，可以帮助设计新的蛋白质和生物活性多肽。这是一项新的 一种名为蛋白质优化进化工具(POET)的技术可以生成一个描述 多肽与其各自活性之间的关系。此外，通过蛋白质进化的循环，我们可以 显著改进模型，从而产生具有显著改进功能的多肽。 将合成生物学方法转化为临床治疗的一个主要挑战是需要改进 活体内与生物回路的通讯。为此，我们将利用 生产蛋白质和多肽，这些蛋白质和多肽可以从细胞读取信息，也可以将信息写入细胞。 在这里，我们寻求改进、测试和实施这一模式，以实现三个相互关联但又独立的目标。在 第一个目标，我们将部署POTE开发一种超灵敏的基于多肽的MRI显像剂，基于 质子交换。我们的初步数据显示，仅通过几个肽进化周期，我们就超过了 最先进的类似多肽。在第二个目标中，我们打算使用类似的方法来开发一部小说 基于T1弛豫的磁共振成像探头。我们将使用代谢工程的方法来表达和加载 用镧系元素的多肽，以及改进后的PEAT算法下一代。最后，第三个目标， 我们将利用诗人发现新的药物和基因递送多肽。我们将利用一个新的平台 用于基因/药物传递，以测试多肽的效率。 所有这三个目标都将从多肽的计算设计开始，然后是体外测试和几个 多肽进化的循环，直到最终多肽被鉴定出来。所有这三个目标都将通过示威来结束 在非侵入性的体内模型中这些多肽在临床相关问题中的应用 成像。 我们期待这种创新的方法将为开发强大的生物活性开辟一条新的途径。 多肽和蛋白质用于解决关键的生物学问题，并用于开发新的诊断和治疗 可以极大地造福于众多患者的方法。

An immense advancement in machine learning and artificial intelligence has transformed many aspects of our lives. The integration of artificial intelligence into the biomedical field allows us to solve complex biological problems that are the bottle neck of developing progressive diagnostic and therapeutic tools. One example is the need to manipulate the amino acid sequence of peptides to improve their function as bioactive molecules. Embarking on these new technologies, we developed a new machine learning tool that is based on a discipline known as “genetic programing” that can assist in designing new proteins and bioactive peptides. This new technology, termed Protein Optimization Evolving Tool (POET), can generate a model that describes the relationship between a peptide and its respective activity. Moreover, through cycles of protein evolution, we can significantly improve the model and consequently generate peptides with substantially improved function. A major challenge of translating synthetic biology approaches to clinical treatment is the need to improve the communication with biological circuits in vivo. To that end, we will leverage the immense potential of the POET to produce proteins and peptides that can read and write information from and into cells. Here we seek to improve, test and implement this model into three related, yet, independent aims. In the first aim, we will deploy the POET to develop an ultrasensitive peptide-based imaging agent for MRI based on proton exchange. Our preliminary data shows that through only few cycles of peptide evolution we surpassed the state-of-the-art similar peptides. In the second aim, we intend to use a similar approach to develop a novel MRI imaging probe based on T1 relaxation. We will use a metabolic engineering approach to express and load the peptide with Lanthanides, and the POET algorithm to improve the next generations. Lastly, in the third aim, we will use the POET for discovering new peptides for drug and gene delivery. We will utilize a novel platform for gene/drug delivery to test the efficiency of the peptides. All three aims will start with computational design of peptides followed by an in vitro testing and several cycles of peptide evolution until the ultimate peptides are identified. All three aims will be ended by demonstration of the utility of those peptides in a clinically relevant question in an in vivo model followed by non-invasive imaging. We anticipate that this innovative approach will open up a new avenue for developing powerful bioactive peptides and proteins to solve critical biological questions, and for developing new diagnostic and therapeutic approaches that can vastly benefit the well-being of numerous patients.