Nicola Hodson takes apart the transport systems in cells to see how they work and how their disruption might cause disease. Here, in her shortlisted article for the Max Perutz Science Writing Award 2012, she invites us into the microscopic city of the cell.
I’m sitting in Cambridge on a Monday morning observing the relentless chaos of commuter traffic. Cargo-bearing vehicles zip in, out and around the city, efficiently delivering goods to their required locations. All this hustle and bustle is essential to the integrity of such a busy city, without it everything would grind to a halt. I pull my chair back from the microscope in wonder, for what lies before me is not actually a city, but a single human cell.
My research focuses on how vehicles transport cargo into, out of and around a cell. A cell, just like a city, needs particular things to keep going. In a city, food needs to be delivered to supermarkets or to families who have ordered their groceries online. Likewise, a cell needs to bring nutrients inside and just like the supermarkets and the online shoppers, it can select exactly what it wants delivering and when.
When the cell requires a particular substance from its environment, for example iron, it can send chauffeurs up to its surface; we call these ‘receptors’. These wait around patiently until their specific cargo drifts by. Once the receptors have collected their cargo, something fascinating happens. The cell surface at the location of the receptor begins to bend inwards, further and further, until it completely detaches, forming a bubble-shaped, cargo-containing vehicle. This vehicle is coated in an intriguing protein called ‘clathrin’ which is stiff and helps the vehicle to maintain its spherical shape whilst giving it the appearance of a tiny football.
Once inside the cell, these clathrin-coated vehicles need to deliver their cargo to the correct location. Considering how many different things a cell needs, a complex and highly developed infrastructure is required to organise it all. Consequently each cargo enters the cell stamped with a unique ‘sorting signal’, which is not dissimilar to a postcode that you would write on a letter or a parcel. This allows cargo within the cell to be sorted in a way akin to what occurs at a Royal Mail sorting office and distributed to exactly where it is needed via an efficient team of delivery proteins.
There are a whole host of different proteins involved in the cargo-sorting process from those that help the cell surface to bend inwards, to ‘motor proteins’ that give vehicles the power to zip around the cell to far-flung locations. My research focuses on identifying new proteins involved in this infrastructure to allow us to further understand how this complex cellular city functions. The reason behind this is because if the sorting network doesn’t work, disaster quickly ensues. It only takes one protein, even one with a seemingly small role, to acquire a mutation and our cargo doesn’t get where it needs to go. Imagine if the supermarkets or petrol stations stopped receiving deliveries, the city would soon be in chaos.
To identify these new proteins, I’m taking a systematic approach. I remove proteins from the cell, one by one, and look for cargo not arriving where it should. Much of the time when I get rid of a particular protein, nothing happens but sometimes all the cargo and receptors get stuck on the surface of the cell and I know I’ve destroyed something that’s involved in the delivery process, like a postman or a taxi company. Then I can put the defective cells under the microscope and start investigating the function of this mysterious protein more thoroughly to find out exactly what it is and what role it plays.
Studying such a fundamental cellular process allows us to slowly, piece by piece, build up a picture of the cell’s interior. Nothing illustrates the importance of the cell’s trafficking infrastructure more than the fact that loss of many of the key proteins results in death before birth. Consequently, the more we learn, the more we can apply the knowledge to understanding human diseases.
A multitude of viruses and bacteria hijack the cell’s transport system in order to invade and cause disease, including the flu-causing influenza virus and the AIDS-causing human immunodeficiency virus. Not only this but defective cargo trafficking in neurons, the cells of the nervous system, has been linked with learning disabilities. Therefore if we understand more about which proteins are involved in the trafficking process, we can learn how to effectively defend our cellular city.
Nicola is a PhD student at the Cambridge Institute for Medical Research.