The Fundamentals of Phagocytosis: Integrating Theoretical Models and Experiments

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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.