A novel in silico framework for early mammalian embryo development

动物是如何从一个受精卵发育成由数万亿个细胞组成的复杂身体结构的，这是一个迷人的问题。一个受精卵必须以某种方式一次又一次地分裂，以产生许多不同的组织类型和身体部位，所有这些都是正确的排列。在植入前的最初几天，受精卵反复分裂，形成一个称为囊胚的球形结构。这种结构通常由几百个细胞组成，大小约为五分之一毫米，但其具体原理仍不清楚。特别是，尽管经过几十年的研究，这一领域仍然充满了悬而未决的问题。这些问题包括如果某些细胞没有正确定位会发生什么以及细胞如何相互交流。如果我们了解了最早期的发展阶段，这将对人类生育、试管婴儿治疗等全球性问题具有重大意义（大多数胚胎在植入前失败）、濒危物种保护和粮食安全（通过猪、牛和羊等动物）。这一领域的研究传统上需要进行大量的实验动物，包括老鼠、兔子、牛、猪和羊。利用动物不仅仅是为了研究动物本身，也是为了研究人类的发展。由于使用人类胚胎存在重要的伦理问题，因此通常使用动物模型。因此，任何减少使用动物的方法都具有很大的价值。这就是这个项目要实现的愿景。我们相信，我们的方法有望将这一研究领域使用的动物数量减少80%。乍听之下，这可能有些奇怪。既然胚胎发育是生物学的一个领域，这些非生物学的学科又有什么用呢？然而，经验表明，结合学科和不同的思维方式可以带来更快，更便宜的进展，并获得仅靠生物学本身无法获得的洞察力。我们的想法是设计一个免费的计算工具（基于数学方法），发育生物学家可以使用它来研究早期胚胎。生物学家将首先使用我们的工具来研究他们感兴趣的问题，而不是从动物身上的测试开始。这将缩小选择范围，并为他们的问题提供答案。这本身就足以取得进展。然而，即使没有，如果仍然有必要使用动物，从我们的计算工具中获得的洞察力可能意味着需要使用的动物数量将大大减少。我们将采用两个关键的设计原则，这将导致一个真正新颖的资源。首先，我们将使我们的工具尽可能易于使用。这将意味着研究小组可以从中受益，即使他们无法接触到数学家和程序员。第二，我们将设计一种适用于许多不同动物的工具。每一种动物都需要做出改变，但基本的方法将保持不变。直到现在，这个资源还没有创建的原因是缺乏高质量的数据。然而，令人兴奋的是，去年，我们在埃克塞特大学的合作者成功地为人类创建了第一个真实的细胞模型系统。这沿着着我们其他合作者提供的老鼠、兔子和牲畜的数据，意味着我们第一次拥有了使方法成功所需的大量数据。最后，为了利用我们的资源提供的机会，我们必须检查它是否适用于人类以及其他动物。为此，我们将与同意成为我们项目合作伙伴的IVF诊所和NHS基金会信托进行互动。

How animals develop from a single fertilised egg into a complex body structure made of trillions and trillions of cells is a fascinating question. A single fertilised egg must somehow divide over and over again to create many different tissue types and body parts, all in the correct arrangement.During this first few days, before implantation, the fertilised egg repeatedly divides to make a ball-shaped structure called the blastocyst. This structure typically consists of a couple of hundred of cells and has a size of about a fifth of a millimetre.The details of how this happens are still not well understood. In particular, despite decades of study, this area is full of unanswered questions. These include what happens if some cells are not positioned correctly and how cells communicate with each other.Answering these kinds of question is of the upmost importance. If we understand the earliest stages of development, this will have great significance for global issues such as human fertility, IVF treatment (where most embryos fail before implantation), conservation of endangered species and food security (via animals such as pigs, cows and sheep).Research in this area has traditionally required experimenting with large numbers (sometimes thousands) of animals, including mice, rabbits, cows, pigs and sheep. Using animals isn't needed just for studying the animals themselves, but also for studying human development. Since there are important ethical issues when using human embryos, animal models are normally used instead.Any approach that leads to fewer animals being used would therefore be of great value. It is this vision that this project seeks to achieve. We believe that our approach holds the promise of reducing the number of animals that are used in this area of research by up 80%.We will do this by using a combination of mathematics and computing. At first this may sound odd. Since embryo development is an area of biology, how can these non-biological subjects be of any use? However, experience has shown that combining disciplines and different ways of thinking can lead to quicker, cheaper progress, and to insight that simply could not be attained by using biology by itself.Our idea is to design a freely-available computational tool (based on a mathematical approach) that developmental biologists can use to study the early embryo. Rather than starting with testing on animals, the biologist will instead first use our tool to investigate their question of interest.This will narrow down options, and suggest answers to their question. This by itself may be enough to make progress. However, even if not and if it is still necessary to use animals, the insight gained from our computational tool is likely to mean that substantially fewer animals will need to be used.There are two key design principles we will adopt, which will lead to a truly novel resource. First, we will make our tool as easy to use as possible. This will mean research groups can benefit from it even if they do not have access to mathematicians and programmers. Second, we will design a tool that works for many different animals. Changes will need to be made for each animal, but the underlying approach will remain the same.The reason this resource has not been created until now is because of a lack of high-quality data. However, excitingly, last year, our collaborators at the University of Exeter managed to create the first realistic cellular model system for the human. This, along with data from mouse, rabbit and livestock provided by our other collaborators, means that, for the first time, we have the large quantities of data needed to make out approach a success.Finally, to capitalise on the opportunity provided by our resource, it is important that we check it applies to humans as well as other animals. To do this, we will interact with IVF clinics and NHS Foundation Trusts who have agreed to be our project partners.