ICP0 and Skyewalker…no, this isn’t an episode of Star Wars!

Published on: Author: the CVR science blog editors

In this blog post, Professor Roger Everett, who retired recently from the CVR after decades spent in Glasgow (157 papers published… and counting!), answers some of our pressing questions in a Q and A with Siobhan Petrie, our communications officer. If you like what you read have a listen to the podcast interview with Roger where PhD students Joanna Morrell and Yasmin Parr talk with the eminent herpes virologist and resident expert in intrinsic immunity – about his career in science, his time in Glasgow and his love of the great outdoors.

Tell me about your background…how did it all start?

I grew up in the Oxfordshire countryside and was always interested in the wildlife in the local ponds and rivers. I was also fascinated when my father told me about the new sewage works he was designing, and how the methane produced by the microorganisms in the raw sewage was used to drive gas turbines to power the whole operation. So it was natural that I was very interested in biology at school. I was also fascinated by understanding how things actually worked, which developed into a more focussed interest in biochemistry, which was the subject of my undergraduate degree.

Was there a key point that made you decide to become a scientist and also to specialise in the field of virology?

I think I was always interested in exploring and discovery, both in the outside world and academically, so it was natural after my upbringing that I focussed towards the sciences. While at University I never believed I had the potential to actually make research a career but it was a dream to strive for, and when the results came in after Finals it seemed more of a realistic goal.

My interest in virology came from a desire to understand biological machines and fundamental processes, gene expression and DNA replication for example, and in the late 1970s bacteriophage provided the best model systems to use for these aims. So I developed a clear plan – do a PhD (well, DPhil actually, it was in Oxford) on bacteriophage with the intention of moving into viruses that infect humans afterwards.

What’s it like heading up a team and leading a programme of research at the CVR…

Challenging but rewarding! Throughout my career in Glasgow, first with the MRC Virology Unit and of course latterly the CVR, the funding has mostly come from the MRC through the 5-yearly review system. This system allows one to spend most of the time on actual research, as once successful in the Quinquennial Review one doesn’t need to continuously write grants, which is great – you can concentrate on what I’ve always thought of as ‘real’ work. The potential downside is that if you are not successful, you simply lose your job. This hard fact is a great motivator, and I can’t think of a better way of doing it – you are simply forced to be continuously productive, creative and imaginative. That’s the challenging bit.

The CVR provides an excellent infrastructure and environment to help you along the way, and of course there are many like-minded people with whom to interact and develop ideas, so the rewards are high. It is also very rewarding to build an effective group and to work with the research assistants, post-docs and students within the group, and then later to watch a number of students and post-docs go on to build successful careers of their own. I must make special mention of Anne Orr, who has worked with me over the past 26 years and who has provided a stable bedrock that underpinned the whole working of the group.

You have worked at the CVR for a very long time and must have seen many changes over the years.  What can you tell me about the way things have changed over the years and the impact that’s had on the way you approach research….

Biological science has changed almost beyond recognition over the past 45 years. My undergraduate textbooks had virtually no DNA sequences in them, simply because there weren’t methods for determining sequences effectively. We have gone from that situation to one in which we are not only able to determine the complete genomic sequence of an individual as a routine operation, but we can also edit the human genome precisely. This is simply astonishing. Techniques and research tools have also developed to a massive extent, with the upshot that we can simply do much more science, far more quickly and to a much greater level of detail and understanding. This massive increase in the power of research, while overall of tremendous benefit, has however some consequences for the scientific community that require a bit of caution. One consequence is that it is now impossible to keep up with the ever expanding literature, so one must be selective in one’s reading.

One pitfall that some fall into is a temptation to do experiments simply because one can, losing sight sometimes of why one is actually doing them. Powerful methods can also produce apparently convincing artefacts, if used without understanding. There is beginning to be a discussion about problems connected to irreproducibility in biological science, and these arise at least in part because of this issue, and also because of undue trust in the authenticity of reagents (e.g. commercial antibodies) or the value of seemingly elegant and powerful but massively unphysiological experimental approaches. Therefore, for my own research, while I have been very happy to adopt modern methods and technologies, I have always felt it fundamental to keep as close to a simple virus infection as possible. It’s amazing how informative simply observing what happens when viruses are put onto cells can be (having tweaked said viruses and/or cells a bit to answer a specific question, of course!).

What have been the biggest highlights of your career?

The best highlights for many a researcher’s career are not connected with professional progress (promotions, publications, etc) but are those totally ‘Wow!’ moments when a genuinely new result comes to light for the first time. I have been lucky enough to have had a number of these over the years. One example came from an analysis of proteins that interacted with ICP0 in an affinity purification approach. We obtained a reliable band on a gel, but in those days it was technically extremely difficult to identify the protein and its gene from that point. We eventually managed it (at one point dunking hybridisation filters into a beaker being heated over a Bunsen, waiting for the background counts to fall off – I loved this type of Heath Robinson improvisation) only to find that the band was a ubiquitin specific protease. At first I was disappointed, having expected to find proteins more conventionally involved in regulating gene expression, but from this finding grew the whole field of ICP0 functioning through the ubiquitin pathway by degrading cellular repressors. Another was the quite unexpected realisation that PML NB components were actively recruited to the sites of parental HSV genomes, which came from a chance observation while gazing down the microscope looking for something else. That really was a ‘Wow, how on earth does that happen!’ sort of moment, and that led to a much better understanding of the fundamentals of the interactions between viruses and PML NBs. Another happy morning that sticks in my memory is when we’d developed a system for inducible expression of ICP0 and used it to test reactivation of quiescent HSV at will. We added the substrate to detect reactivated expression and watched as the cells turned blue. Wow! It works! And again a new doorway opened for novel research avenues. It is these exciting moments that I will miss most in retirement.

I’m sure you’ll maintain a key interest both in the field but also in the work of the CVR.  What are you excited about or hope for in the future?

The field moves so quickly these days that it will be difficult to keep up. It will be really interesting to follow developments in the HSV latency, in particular whether PML NBs play a role in latency in human neurones as we would predict from our cultured cell studies. There’s some new and very promising work going on in this direction. In the longer term, it would be really neat if knowledge of the mechanisms of action of key herpesvirus regulatory proteins, such as ICP0 of HSV and IE1 of HCMV, can be harnessed to develop new antivirals. We had a go at a project along these lines a few years ago, but I believe that the potential for this is stronger and better understood now. For the CVR as a whole, I am sure it will go from strength to strength, but I hope also that it retains a place for detailed interest-led basic science projects, as these are one of the bedrocks of fundamental advance.

Do you feel like you’ve achieved everything you hoped to in your career?

That’s a difficult one. I’ve always followed where the science has led me, rather than try to force it towards my own agenda, so I certainly don’t feel that I’ve retired with unfulfilled goals. And it was always the basic interest that motivated me rather than professional advancement, so I never intended to strive towards high profile jobs (that, and a realisation that I probably wouldn’t be any good at them). Some might view that as unambitious, or even selfish, but I hope instead that I’ve left a legacy of research that is genuinely useful and informative, and that will stand the test of time. I’ll be happy with that.

What advice would you give to early career scientists…

That’s a big question! So much to say, most of it pretty obvious and in no particular order: Be enthusiastic; work hard; be persistent; think about your project very hard; be led by observation and interpretation rather than hypothesis (then test the hypothesis arising from the interpretation); spend time to relax out of the lab, but use this also to think about and analyse your work in a more relaxed environment; be critical of your own experiments (if you’re not, the reviewers will be); aim for really high quality data – don’t be content with a messy gel; a technically competent experiment, as a general rule, never ‘doesn’t work’, it indicates the ideas behind it aren’t quite right; in other words, aim to explore what’s really happening, rather than ‘prove’ your (or your boss’s) favourite hypothesis; be original and innovative – avoid ‘me too’ or obvious experiments; avoid jumping on bandwagons – you’ll likely land up playing the triangle rather than the trombone; aim to be really good at something to create your own identity; don’t be afraid to admit being wrong (it happens); follow what the science is telling you, which is not necessarily the same as what is commonly assumed; have a clear idea of why you’re doing the work, and what the fundamental underlying aims are (you need to understand both the woods and the trees); don’t get too hung up on publishing in high profile journals (this can be very damaging – remember that it’s the impact of the actual paper that’s important, not the journal in which it is published. After all, if we had to rely on what’s published in Nature as our sole source of information, we wouldn’t know very much in our field, and quite a lot of it would be wrong!); finally, if you really want to follow a career in academic science, heed some of the above and just keep at it – it may seem almost impossible to get one of those rare staff positions, but it’s always been like that and if you’ve got what it takes you’ll get there if you’re persistent. If you give up you won’t.

Lastly – how do plan to spend the next chapter of life…

It will come as no surprise to anyone who knows me that I intend to spend even more time climbing, skiing and exploring mountains in the UK and further afield. I had 3 weeks in Greenland just after retiring, which was great, and my wife and I have just had a week of fabulous weather in Skye, and we’ve planned trips to trek in Iceland and climb in the Alps in the summer. Being able to do this type of thing won’t last forever, of course, but we intend to make the most of it while we can. But there’s more to life than just enjoying oneself, so I’ve a few other projects as well. I hope to progress towards a winter Mountain Leader qualification (more for interest than anything else), and perhaps I’ll also get involved in the outdoor community in a volunteer capacity, probably in conservation projects in the Scottish hills (we have to look after them, they are precious). Oh, and I’ve also got a few papers to write. I’m certainly discovering the truth behind what a lot of retired people say – ‘don’t know how I ever managed to find the time to work’!