Professor Paul Digard on understanding flu viruses

How would you summarise your background and your research?

I'm originally from Guernsey, in the Channel Islands. I lived in Cambridge and did my training there before moving to Roslin 12 years ago.

I'm a molecular virologist, and that's what I've done for my whole career, for nearly 40 years now. The core of what I do is trying to understand the molecular and cellular biology of how viruses replicate. I mostly focus on researching flu viruses, but I have worked on other viruses, including SARS-CoV-2.

Over the years, I've also done practically orientated work about how we deal with viruses in hospital settings, such as how to properly disinfect surfaces, how we can control aerosols and droplets, as well as aiding in the development of vaccines and antivirals.

Where we really want to be able to get to, is trying to predict how viruses will evolve. There's a huge diversity of flu viruses out in the wild, and we need to be able to risk assess strains as they appear, and try to predict how a strain will evolve. This is a team effort; I’m working on this with lots of other researchers with a diversity of skills I don't have.

How do you look at the molecular biology of a virus?

For viruses such as flu and Covid-19, we grow samples in the lab under containment. We work with the virus in cell culture, watch it replicate and measure how well it replicates. A foundation of what we do is a technique called reverse genetics, where we can recreate a virus from scratch using cloned synthetic DNA. That means we can change the virus, make mutations in the virus and test what they do.

To give you an example from the current moment, anybody who's looked at the BBC over the last couple of years will have seen the bird flu is a problem in poultry and wild birds, and potentially in people. We get the gene sequences of new variants as they appear in the wild, and my team and I try to risk assess them based on what we know about how flu works. If a particular variant is more and more prevalent, we can take a cloned and modified version of that virus which is a safer version to work with, and we study how the variation changes the virus behaviour.

What are you working on at the moment?

My main focus is always on flu viruses. Lately, I’ve been working on avian flu because nowadays that’s a pressing issue, but it could be human flu tomorrow. For example, cow flu is currently a big problem in the USA, with potential to become much worse, so my work is pivoting to that right now, and in the future to whatever flu virus is evolving to be a significant problem.

What made you want to study flu viruses?

I've always been fascinated by viruses in general. As an undergraduate, I didn't actually want to research flu, I wanted to be a herpes virologist when I was a youngster, but when it got to doing a PhD, I had the opportunity to do a PhD studying flu at Cambridge University, in a work environment I knew I would enjoy.

It's surprising when you look back now, but In the 1980s, flu was not of huge public health interest; there was a genuine view that maybe the cycle of flu pandemics had stopped for some reason. That all changed in 1997 when bird flu first appeared as a serious human pathogen. Ever since, flu has been the most interesting virus in the world to me.

Can you share any research breakthroughs in your recent work that you think would advance knowledge in flu transmission or prevention?

I was recently involved in research with my colleague Dr Rute Pinto, where we made a discovery that advanced our understanding of the immune defences that host species can put in place to block flu infection. She identified a human gene that acts as a barrier to avian flu, and it's one of the reasons why we don't get bird flu all the time. Dr Pinto also identified how the virus evolves to get around those defences, so it's not a perfect barrier, but it gave us another set of genetic sequences to look for in new virus strains, which can help us predict virus behaviour.

Do you have a favourite project that you've worked on?

The projects that I really like are interdisciplinary - working with colleagues with totally different areas of expertise is really thought provoking and exciting. However, my biggest legacy, and the one I’ll always be most proud of, is the people I’ve trained over the years. Research findings can change and get outdated after a few years, but seeing PhD students and postdocs advance in their careers and go on to do amazing things on their own will always be my favourite part.

How does your work interact with public health policy?

During the Covid-19 pandemic I ended up working with colleagues in the University’s School of Engineering. They had the expertise to measure individual respiratory droplet particles that come out of people's mouths when they talk, sing, cough or sneeze. We measured how well masks worked at blocking those, and it was a useful project. It gave a visual illustration, as well as measurements that said that, yes, even a cheap single layer polyester buff pulled up over your face blocks the bigger respiratory droplets and could help stop the virus from spreading.

We’re doing further development of that project, led by a colleague from Edinburgh Medical School, where we're going to measure respiratory droplets and virus load coming out of infected patients in hospital, which will tell us whether we need to worry about aerosols or the bigger respiratory droplets. That can influence how we deal with the containment and protection of the staff tending them.

Other ways we feed directly into policy is from the animal health side of things. I'm a member of the DEFRA Science Advisory Council Subgroup on Emerging Disease (SAC-ED). We provide an overview of the evidence and the questions that DEFRA might need to consider for them to write effective policy.

As a scientist, what kind of challenges do you face in your work?

The big challenge that molecular virologists working on human pathogens are currently facing is controversy over gain of function research.

We modify viruses using reverse genetics, and if we make changes that we expect will let the virus do something it can't do normally, that's gain of function, and it's potentially dangerous. However, the knowledge that can be gained from these types of experiment can also be very important if we are to understand how to fight evolving viruses. There's an argument going on about what constitutes gain of function, and what sort of checks we have in place to make sure that things are controlled, and that research is done safely. In my own lab, we adhere to the highest possible safety standards when undertaking this sort of work. If possible, we will ask the research question using a "loss-of-function" approach, where we try to mutate the virus to become less pathogenic.

What measures do you take to ensure research is done safely?

All our work is fully licensed. If a scientist wants to genetically manipulate a virus, they need to have formally told the Health and Safety Executive what we're planning to do, and come up with a risk assessment for it. Everything we do is covered by national and local risk assessments. There's always a level of oversight, and it's something we monitor and consider on a weekly basis. When we come to start making new viruses, we need to consider whether we expect it's going to significantly increase risk, and we mostly end up working with a surrogate for the virus, not the real virus. You can think of viruses like little machines; we can take the engine out of the virus and look at it by itself, without the body work around it, and it’s completely safe.

Sometimes we’ll need it in an infectious form. At that point, we use components from a vaccine strain. which has a huge track record of being non-dangerous for people, or animals for that matter. We think about all safety hazards, and we don't do things trivially.

Do you have any advice for fellow scientists on how to engage with the public?

There's a lot misinformation surrounding scientific topics, and often we need somebody who understands a topic well to give a different view. One piece of advice is to not be tempted into straying away from the subjects you really know about. A lot of scientists want to fight misinformation, but the only way around that is sticking to their areas of expertise and discussing data they are confident in. My other piece of advice is to be aware of who you are talking to, and what their agenda is.

If you weren't a scientist, what would you like to be doing?

All my family over the past couple of generations worked in print media. I was adamant growing up that I wasn't going to write for my living, like the rest of my family. I did end up writing, just different stuff. In another life, maybe I'd have been a journalist.