Understanding size-robust self-organization of morphogen gradients

背景自然界存在着令人难以置信的多样性的生物结构。这些结构复杂但精确，例如，人类的手必须具有正确的大小和形状，并在正确的位置和适当的数量包含细胞类型(例如神经、肌肉、骨骼)。与人造结构不同，生物结构并不是完全形成的；我们都是从单个细胞开始生命的。相反，生长、图案形成和形状变化将微小的胚胎转变为复杂的动物，这一过程被称为发育。卵子发育动物或器官，细胞必须知道它们在其中的什么位置，才能成为正确的细胞类型并激活正确的基因。人们早就知道，细胞使用分子来测量它们的位置，类似于分子GPS。一般的想法是，分子信号是在器官外部的特定区域(信号中心)产生的，然后逐渐渗入，形成浓度梯度。如果细胞感觉到高浓度，那么它就知道自己离信号中心很近，并激活相应的基因，反之亦然。然而，近年来，我们对这一过程的理解发生了戏剧性的变化。虽然细胞确实使用分子梯度来测量它们的位置，但我们发现，如果最初被认为是必不可少的信号中心被移除，这些梯度仍然会形成。换句话说，细胞不只是被动地对梯度做出反应，它们还积极地参与到制造梯度的过程中，这一过程我们还没有完全理解。这就像是一个满是水的浴缸，在你没有接触到它的情况下就形成了波浪。控制发育的分子梯度是如何在没有外部信号中心的情况下形成的？为什么它很重要？所有动物在其发育过程中都重复使用分子梯度；因此，了解它们是如何形成的是一个至关重要的问题。这个问题也具有现实的现实意义。最近发现的有机化合物--可以从人体干细胞体外培养出来的器官--显示出了巨大的前景，因为它们可以用来模拟人类疾病，并为器官替代疗法铺平道路。然而，目前的有机化合物非常容易出错，而且往往无法形成器官发育所需的分子梯度。我们的工作将确定减少这些错误并提高有机类化合物在生物医学中的有用性的策略。我们将结合数学和实验来建立分子梯度的定量模型，并使用这些模型来预测如何使有机化合物不那么容易出错。就像我们需要对材料物理学的精确理解来设计可靠的桥梁和建筑一样，我们需要对发育生物学的定量理解来对可靠的器官和有机物进行生物工程。我们的计划我们将采取两种相辅相成的方法。首先，我们将详细研究一个已经可靠地形成梯度的有机体系。这是包括人类在内的动物物种中最早形成的梯度之一，由一种名为Nodal的信号控制。我们选择在斑马鱼胚胎有机体(称为Pescoid)中研究这一点，这是定量方法的理想选择，因为我们可以实时观察梯度的形成，并能够精确地操纵它们，而涉及的基因与人类的基因非常相似。在建立了节点梯度的精确数学模型后，我们将使用这个模型来理解为什么假斜面如此可靠地产生梯度；我们预计答案在于单个细胞移动的程度。同时，我们将研究其他已知在各种器官/有机体中自组织的分子梯度。通过建立许多不同分子信号的模型，我们将询问健壮的节点梯度背后的原理是否也适用于其他系统，从而确定可靠地制造体外器官的一般工程原理。

BACKGROUNDThere is an incredible diversity of biological structures throughout the natural world. These structures are complex yet precise e.g. a human hand must be the correct size and shape, as well as containing cell types (e.g. nerves, muscle, bone) in the right place and the right amounts. Unlike man-made structures, biological structures are not created fully-formed; we all began life as a single cell. Instead, growth, patterning and shape-changes transform a tiny embryo into a complex animal, a process known as development.OVERALL QUESTIONAs an animal or organ develops, it is essential that cells know where they are within it to become the correct cell type and activate the right genes. It has long been known that cells use molecules to measure their location, akin to a molecular GPS. The general idea is that a molecular signal is made in a specialized zone outside the organ (a signalling centre), which then gradually seeps in, forming a concentration gradient. If a cell senses a high concentration, then it knows that it is close to the signalling centre and activates the appropriate genes, and vice versa. However, our understanding of this process has changed dramatically in recent years. Whilst cells do measure their position using molecular gradients, we are finding that these gradients still form if signalling centres, originally thought to be essential, are removed. In other words, cells are not just passively responding to the gradient, they are actively involved in making it, a process that we do not yet fully understand. This would be like a bathtub full of water forming waves without you ever touching it. SPECIFIC QUESTIONHow do the molecular gradients that control development form without external signalling centres?WHY IS IT IMPORTANT?All animals use molecular gradients repeatedly throughout their development; understanding how they form is therefore a question of fundamental importance. This question also has real practical significance. Recently discovered organoids - organs that can be grown outside of the body from human stem cells - show great promise, since they can be used to mimic human disease and pave the way for organ replacement therapies. However current organoids are highly error-prone and often fail to form the molecular gradients necessary for organ development. Our work will identify strategies to reduce these errors and improve the usefulness of organoids to biomedicine. OUR APPROACHWe will combine mathematics and experiments to build quantitative models of molecular gradients and use these models to predict how organoids can be made less error-prone. Just as we need a precise understanding of materials physics to engineer reliable bridges and buildings, we need a quantitative understanding of developmental biology to bio-engineer reliable organs and organoids. OUR PLANSWe will take two complementary approaches. First, we will study in detail an organoid system which already forms gradients reliably. This is one of the earliest gradients to form in animal species, including humans, controlled by a signal called Nodal. We choose to study this in zebrafish embryo organoids (known as pescoids), ideal for quantitative approaches since we can watch the gradients forming in real-time as well as being able to precisely manipulate them, whilst the genes involved are very similar to those in humans. After building an accurate mathematical model of the Nodal gradient, we will use this model to understand why pescoids make gradients so reliably; we expect that the answer lies in how much individual cells are moving around. In parallel, we will study other molecular gradients known to self-organize in a variety of organs/organoids. By building models of many different molecular signals we will ask whether the principles behind robust Nodal gradients also apply to other systems, and therefore identify general engineering principles to reliably make organs outside the body.