David Stuart: Structural biology and vaccines

Q: What is structural biology?

DS: If you want to understand structural biology you need to think about how you would understand how a car works or anything else that is complicated. You need to understand the individual pieces, how they fit together and how the machinery works? Structural biology is trying to do that in a very detailed way for organisms like us, and to do that you need to go in to terribly fine detail. We are made up of millions of cells and each of those has incredibly intricate machinery inside that operates at a molecular level. Structural biology is trying to understand how those nano-machines work and how they affect the complexity that is life.

Q: How can structural biology help us improve vaccines?

DS: Structural biology is in principle a great way to try and improve vaccines because the way that vaccines work is a very physical process. The basis of a vaccine being effective is that the virus or bacteria that the vaccine is going to control is physically recognised by molecules that are produced in your body. Those molecules recognise, attach to, and lead to the elimination of the virus or bacteria. If we understand the structure we can see the chemical basis of that recognition and we can then try and redesign, or design a 'mimic', of the pathogen that might elicit a more effective response from us to the actual virus or bacteria. We can make a mimic with better physical properties, or it might be that something about the structure leads to antibodies that we produce to neutralise not just that exact pathogen but also closely related pathogens. We therefore might be able to, by clever design, produce a vaccine that will give slightly broader protection than you would generally get with a specific virus or bacteria.

Q: Can you give us an example of this kind of work?

DS: For many years the World Health Organization has had a programme to try and eradicate polio virus from the globe. That has gone pretty well and there are now only a few countries where people still get polio, largely thanks to mass vaccination. However, it's going to be hard to completely stop vaccinating because we immunise people with vaccines that include live, attenuated viruses. One consequence of this is that within populations there are individuals that even though they have been vaccinated still have polio virus replicating inside of them. These people then shed the virus so if we stopped vaccinating there would be the potential for the virus to completely explode in the unvaccinated population. We are looking at trying to understand the structure of the polio virus so that we can make a safe synthetic version of the virus. It then won't contain the viral genome and will not be able to divide. It won't be a virus rather it will just be a synthetic copy. If we could replace the current vaccine with a synthetic vaccine like this then there would be no chance of the virus replicating in people who have been vaccinated. It would be quite a useful tool in the endgame of trying to move to a world where not only have we eliminated polio as a disease but where we have eliminated it as a virus and as a potential threat. One could imagine that eventually we would then be able to stop vaccinating against polio altogether.

Q: What are some of the most important lines of research that have developed in the last 5-10 years?

DS: The last few years have seen some really interesting developments particularly in how we can image living systems. There have been some wonderful advances in light microscopy so that we can now track viruses as they interact with living cells. Also there have been developments in electron microscopy, now a fantastically powerful technique, which can give us the detailed information that we need to be able to look at these pathogens and try and design better therapies against them.

Q: Why does this line of research matter and why should we put money in to it?

DS: I hope that it will make a difference in terms of people's health and in terms of animal's health in the long run. It's very important to realise that most of the science that people do doesn't lead to an immediate new drug. If you look at where the new therapies come from they maybe come from things that people started working on 25 years earlier. There is a very long, slow burn before you get a result. It is important to recognise that you do the fundamental research and it may be for you or others to do the translational impact. But it will be there eventually, as we see from new therapies. At the time when you are first doing the research it you can't predict how it will turn out or how it will impact on human health.

Q: How does your research fit in to translational medicine within the department?

DS: It fits in in some ways but there also a lot of basic elements to it that are a bit separate. We aren't there at people's bedsides with these things and there is quite a gap. The people we tend to work most closely with are the people who are developing the vaccines. However it is also important to have within the University the ability to do clinical trials and test vaccines, which is one of the strengths of Oxford. There are a lot of things that we do that don't immediately translate but some things do.