Cells constitute the smallest autonomous units of life. The tightly regulated structural and functional organization of a cell is currently only rudimentary understood. Professor Grünewald uses electron cryo tomography in combination with other techniques to analyze selected aspects of this highly ordered network of protein complexes in situ.
Understanding the entirety of a virus’ ‘life cycle’ requires an understanding of its transient structures at the molecular level. Using imaging techniques allows us to understand the communication between the virus and the components of the cell it is infecting, which can ultimately help to treat infectious diseases.
Ultimately, medical research must translate into improved treatments for patients. At the Nuffield Department of Medicine, our researchers collaborate to develop better health care, improved quality of life, and enhanced preventative measures for all patients. Our findings in the laboratory are translated into changes in clinical practice, from bench to bedside.
Q: What happens when a virus invades our cells?
KG: When a virus infects a cell, a cell is typically something we don’t think of. If something infects a body, then you think that in a body we have organs, tissue, and the cell is the smallest thing that the virus is actually facing. So the virus is faced with a cell that has a boundary and then has a defence mechanism. The virus is actually first faced with this physical barrier - the plasma membrane and has to overcome this. The virus has developed a number of mechanisms to do this; these are also mechanisms that the virus has learnt from the cell because internally in the cell there are cell-cell fusions like little vesicles that fuse all the time as little messengers. So the virus actually hijacks these things and uses this to come into the cell and then the whole program of the life cycle starts. The virus propagates inside the cell to have offspring to infect a neighbouring cell. If you go back to the level of the whole body, that’s how virus spreads.
Q: What techniques do you use to study these mechanisms?
KG: We use a range of techniques to study this and I think the beauty is of combining these. Our core techniques are imaging techniques. If you think of imaging techniques, microscopy, as what people see as images. This is typically not sufficient because viruses are in the size range of the sub-micro-meter and that’s where the resolution ends for us with microscopes. So if you have a labelled virus you can get an idea of how it moves inside the cells. But we’re using something called cryo-electron tomography and this actually allows us to get nanometre resolution images in 3D of objects that, in our case, are kept very native so we can study it in its native environment without destroying that and having the resolution to follow a single virus.
Q: Can your research help us treat infectious diseases?
KG: Yes it definitely can. Having the resolution power makes small things visible so we are now able to follow these diseases at a molecular level, so this is inside the cell. We are seeing the communication between the virus and viral components with the cellular components and it’s this type of war the virus tries to overcome. The cell defence on the other hand tries to use cellular mechanisms to reprogram the cell to actually help in the propagation of itself. So understanding at this level we can then understand what an infection is about. It’s these little details that make it global.
Q: What are the most important lines of research that have developed over the past 5 to 10 years?
KG: In the past 5 years we’ve been able to actually develop the tools and the machineries, so we’ve first established these tools that allow us to really look at the viruses themselves. Prove that this would work so we are able to show the viral outer structure to resolution that wasn’t possible for this pleomorphic virus as before. Then we went a step further to look at the virus host interactions and establish cellular systems that allow us to do this, and even sub-cellular systems to look at molecular interactions in more detail. Now we’re looking at a viral life-cycle and focus on specific aspects of this - viral entry, transport inside the cell, replication of viruses, exit of viruses from the cell. We are now focusing on these and this gives us clues first of all on the viral infection but back also on cell biology.
Q: Why does your line of research matter, why should we put money into it?
KG: I think we are studying a group of viruses which is extremely interesting. Herpes viruses is one of our model systems. Herpes viruses span a number of viruses that are very relevant for humans - you can think of chicken pox, everyone knows chicken pox; we know the herpes simplex virus causes cold sores in the facial region and in severe cases encephalitis, it can even lead to death. They are also in the same group as tumour viruses so it’s a very important study. I think working in this group of viruses is very interesting as a pleomorphic group. On the other hand, if you look into the specifics of herpes simplex one of our model organisms, there are 80-95% of the human population infected depending where you look on the globe, but only 20% develop lesions or similar symptoms. But we still think it’s very relevant - it’s a large part of the population and it’s a disease that we can’t cure; once you acquire it, it will be with you forever so it’s an important group of viruses.
Q: How does your research fit into translational medicine within the department?
KG: We’re currently working on the cellular level - understanding the molecular mechanisms on how the virus interacts with the cell. This is basic research at this point but if you for instance look at virus entry: if we understand how virus entry works at a molecular level, if we know the players from the cell and the interactions with the virus in the inside, if we can interfere with this process, then we can keep the virus out of the cell and ultimately out of our bodies and this is where we will focus. It’s not yet there, we are working towards this and I think in a horizon of 5 years we will have enough understanding that allows us to tackle this.