The Fundamentals of Phagocytosis: Integrating Theoretical Models and Experiments

细菌、病毒和其他病原体每时每刻都在轰炸我们的身体。如果我们不回应，这很快就会导致死亡。我们的免疫系统使用一系列复杂的方法进行反击，目的是尽快摧毁入侵者。其中一种方法是吞噬作用，这个词源于古希腊语，意思是“吃”和“细胞”。这是最令人印象深刻的免疫防御机制之一，涉及免疫细胞首先追逐病原体，然后在一个称为吞噬的过程中将自己包裹在入侵者周围。一旦进入体内，病原体就会被特殊的酸性化学物质摧毁。当然，病原体不会袖手旁观，等待被摧毁，这会导致我们的身体与外来入侵者之间持续不断的战斗。例如，细菌的形状对免疫细胞将其清除的容易程度有很大影响。此外，免疫细胞攻击病原体的方向可以决定入侵者是被摧毁还是活着去另一天战斗。这就引出了一个从未得到解答的有趣问题：哪些病原体形状最容易被免疫系统消除，哪些是最难消除的？回答这个问题并不容易。简单地在显微镜下观察吞噬作用不会有多大帮助。相反，在这个项目中，我计划用数学、计算和传统生物学相结合的方法来回答这个问题。从表面上看，这听起来有点奇怪。数学和计算机与免疫系统有什么关系？然而，无数的例子表明，将数学与生物学相结合可以极大地加快科学进步。这是因为数学和计算可以快速地考虑用传统生物技术很难或需要很长时间才能解决的问题。使用这一学科的组合将使我第一次能够研究病原体的形状、病原体的大小和免疫细胞攻击的方向是如何影响吞噬作用的。这方面最有趣的应用之一是药物输送。我们通常通过吞下药片或向血液中注射某种东西来服药。这样做的问题是，这种药物几乎立刻就会进入我们体内的任何地方，甚至到了不需要它的地方。最近人们正在研究的一种更好的方法是使用非常(非常！)容纳药物的小容器，即所谓的微粒药物载体。这些药物容器(通常比人类细胞和细菌还小)可以注射到人体内，并直接瞄准需要它们的地方。此外，由于容器需要时间来分解，它们可以用来在几小时、几天甚至几周的时间内缓慢释放药物。开发微粒药物载体的主要挑战之一是，我们自己的免疫系统经常将它们识别为异物，并在它们有用之前将其摧毁。现在需要的是一种设计这些药物载体的方法，使这种情况不会发生。最令人兴奋的新方法之一是选择药物容器的形状，这样免疫系统就不会摧毁它。这正是我将在这个项目中做的：我将确定一系列人体难以摧毁的形状，这将导致未来更好的微粒子药物设计。然而，这项工作不仅仅是药物设计。有许多医学状况与吞噬功能缺陷有关。例如，癌症是指我们的免疫系统无法识别和摧毁我们自己的有缺陷的细胞。而狼疮，几乎完全不被理解，它涉及到我们的免疫系统攻击健康组织。在这个项目中，通过更多地了解吞噬作用是如何工作的，更好的方法来检测和治疗这类疾病将成为可能。

Bacteria, viruses and other pathogens bombard our bodies every second of every day (and night!). If we didn't respond, this would quickly lead to death. Our immune systems fight back using a whole host of sophisticated methods aimed at destroying the invaders as quickly as possible. One such method is phagocytosis, a word that derives from the Ancient Greek for "eating" and "cell". This is one of the most impressive immune defensive mechanisms and involves immune cells first chasing pathogens and then wrapping themselves around the invader in a process called engulfment. Once inside, the pathogen is then destroyed using special acidic chemicals.Of course, the pathogen doesn't sit idly by and wait to be destroyed, which leads to an on-going battle between our bodies and foreign invaders. For example, the shape of a bacterium has a huge effect on how easily it can be removed by immune cells. Also the direction that an immune cell attacks the pathogen can make the difference between the invader being destroyed and living to fight another day. This leads to a fascinating question that has never been answered: which pathogen shapes are the easiest for the immune system to eliminate, and which are the hardest?Answering this question is not easy. Simply looking at phagocytosis under a microscope doesn't help much. Instead, in this project, I plan to answer this question using a combination of mathematics, computing and traditional biology. On the surface this sounds a bit strange. What do mathematics and computers have to do with the immune system!? However, numerous examples have shown how combining mathematics with biology can vastly speed up scientific progress. This is because maths and computing can quickly consider questions that would be very difficult or take a long time with traditional biological techniques. Using this combination of disciplines will allow me, for the first time, to study how phagocytosis is affected by pathogen shape, pathogen size, and the direction of immune cell attack.One of the most fascinating applications of this is to drug delivery. We normally take drugs either by swallowing a pill or by injecting something into the blood stream. The problem with this is that the drug almost instantly goes everywhere within our body, even to places where it is not required. A much better approach, which people have looked into recently, is to use very (very!) small containers that hold the drug, so called microparticle drug carriers. These drug containers (which are often even smaller than human cells and bacteria) can be injected into the body and directly targeted to where they are needed. Also, since the container takes time to break down, they can be used to slowly release drugs over a period of hours, days or even weeks.One of the main challenges in developing microparticle drug carriers is that our own immune systems often identify them as foreign bodies and destroy them before they can be useful. What is needed is a way to design these drug carriers so that this cannot happen. And one of the most exciting new avenues for this is to choose the shape of the drug container so that the immune system cannot destroy it. This is exactly what I will do in this project: I will identify a list of shapes that the body finds hard to destroy, which will lead to better design of microparticle drugs in the future.However, this work is not just about drug design. There are numerous medical conditions that are related to deficiencies in phagocytosis. For example, cancer is the inability of our immune system to identify and destroy our own defective cells. And lupus, which is almost not understood at all, involves our immune systems attacking healthy tissue. In this project, by understanding more about how phagocytosis works, better methods for detecting and treating such diseases will become possible.