Position: Professor of Virology, University of Oxford
Research focus: virus pathogenesis and evolution
What do you love about viruses?
I’m not sure “love” is the right word – I think I just grew to like viruses eventually, as my original involvement in them was really just chance. A very kind microbiology department in Southampton Medical School let me do a summer internship in their research labs when I was a spotty undergraduate medical student (worked on HSV antiviral resistance). And that pre-determined what I did for my PhD (emergence of HIV-1 in Edinburgh) and then my post-doc (HIV-1 evolution with Andrew Leigh Brown) and so on thereafter. So there was really no escape!
What are you currently learning?
Spare moments learning Python 3 – part of a project to bring obscure single OS sequence analysis software (eg. SSE) to a wider community platform.
What is the most interesting question or challenge in science that is still unanswered?
Not virology, but thinking more broadly, understanding what’s going on in the real world behind the veil of mathematical modelling developed for quantum theory and particle physics, with all their intrinsic paradoxes. However, like a goldfish trying to understand what happens outside his glass bowl, we may never be able to go much further than to wonder what happened to Schrodinger’s cat in its box.
What is the coolest thing about your research?
Virus classification, which I am often associated with after HCV is definitely not cool, and not sure it’s actually research!. I think previous work, and in my case hopefully future work (grant gods permitting) on cellular pathways that restrict viruses at the level of nucleotide composition and RNA structure. These include ZAP and RNA editing pathways and represent major extensions to existing ideas about innate immunity and are collectively pretty cool. The shaping effect these have on RNA virus evolution is pretty cool too.
For which project idea are you still looking for a cooperation partner?
The extent to which of host cell editing of RNA viruses can restrict their replication and host ranges and the ways in which viruses can evade these potentially highly potent antiviral pathways. Well explored for HIV-1 and other retroviruses but the pathways and mechanisms likely go wider into RNA viruses too. A combination of wet-lab virology, immunology, bioinformatics and evolutionary biology.
What was your biggest achievement, and what your biggest failure?
In terms of citations, I suppose my greatest achievement was the rather mundane task of classifying HCV in what were then six genotypes and developing a nomenclature for them that is still used after 25 years. However, I’m not sure that is really a scientific “achievement”.
The most recent and strangest discovery occurred on a boring afternoon confined to home during the first COVID lockdown. Looking at the very early sequence data for SARS-CoV-2, playing around with SSE I noticed the strange preponderance of C->U polymorphisms in genome sequences, not sequencing errors, but in retrospect, likely the effect of an as yet poorly understood RNA editing mechanism potentially analogous to APOBEC-mediated error induction in retroviruses. I thought the word “rampant” to described this excess of mutations in SARS-CoV-2, and since detected in other RNA viruses, was quite appropriate in the title of the paper I since published describing this phenomenon.
My biggest failure was not getting funding to investigate this phenomenon biologically, and the broader context of how host pressures drive virus evolution at the RNA level, such as dinucleotide composition and secondary structure. Virus evolution isn’t just neutral random drift and its simplistic modelling nor is it primarily about Darwinian immune escape of T cell epitopes or changes in host receptor binding.
Which scientific topic (outside of your field of research) do you think should have more scientific attention?
The evolutionary origins, pathways and antiviral mechanisms of innate immunity in the 25 or more animal phyla (out of 33) that to date have barely been investigated. Along with knowledge of the viruses that infect them (virtually zero). Identification of diversity and commonalties of mechanisms is key to understanding how humans and other mammals ended up with our current immune repertoires, and how nature might teach us about novel mechanisms that might be exploited to tackle infectious diseases. Seems like a good grant application!
If you had the option to advise a younger version of yourself, what would that be?
A rather difficult question and criticism of my younger persona is not intended! However (as general advice that I have always followed – no really!!), it’s important to be effective and thorough in what you do and publish, use multiple approaches to address a problem (they can’t all get stuck at the same time), and learn from others working in your field rather than competing with them. Develop and maintain broader interests in your subject, but at the same time don’t be “a jack of all trades, a master of none”. And showing my age, it’s your family and friends who will care for you and miss you when you’ve left, not the Infection and immunity Board of Wellcome Trust, or the Nuffield Department of Medicine, so keep a perspective on the things that really matter.