An interview with Professor Martin Ryan

February 2020

Professor Martin Ryan is based at the University of St Andrews, Scotland. He is a member of the Microbiology Society and was awarded the Unilever Colworth Prize in 2017 for his work on the 2A protein co-expression system. In this interview, he tells us more about his research to date and how he is collaborating with other institutions to develop a vaccine for foot-and-mouth disease.

© Martin Ryan

Tell us about your research.

Presently, I am fully committed to the development of live, attenuated Foot-and-mouth disease virus (FMDV) vaccines. We are using synthetic biology to redesign the FMDV genome to include high numbers of synonymous mutations which we, and many others, have shown attenuates viruses – not just FMDV. This project is a collaboration with colleagues at The Pirbright Institute and universities of Leeds, Edinburgh and Dundee; but also veterinary laboratories in Vietnam, China and India. Some work on 2A continues – mainly identifying the breadth of sequences that constitute active 2A or 2A-like sequences in virus and cellular genomes, and their acquisition during evolution.

You have previously given talks on a new generation of live, attenuated, FMDV vaccines. Can you tell us more about what you have learnt about the effectiveness of these vaccines and their potential impact on eradicating certain diseases?

It’s early days yet; FMDV has six circulating serotypes (O, A, Asia1 and SATs1-3) each comprising many strains. We are now testing a generic attenuated virus rescue system, which we hope will be applicable to any serotype/strain of FMDV. This is essential, since one must vaccinate against the different FMDV topotypes found across different regions of the world.

Cheap, effective disease control would be fantastic – the dream outcome would be the eradication of FMDV. What is clear is that this cannot be accomplished by the use of present killed (chemically inactivated) vaccines; since this vaccine must be administered by injection and wild animal reservoirs of virus present a strategic problem.

Eradication is, however, feasible – however remotely – with live attenuated vaccines. Could the classical flow of fully pathogenic viruses from wild to domestic animals be reversed, such that attenuated viruses flow from (live attenuated virus) vaccinated domestic animals, to wild animals?  The next few months and years will provide answers to these questions.

In addition to your research on vaccines, you also spent some time at The Pirbright Institute, working on foot-and-mouth disease. What were the key outcomes of this research?

Whilst at Pirbright, I initially worked on methods to produce virus-like particles from sub-genomic, non-infectious complementary DNA (cDNA) constructs. FMDV produces all of its proteins from a single, long, open reading frame (ORF). This polyprotein is processed by virus-encoded proteinases (Lpro and 3Cpro), together with 2A (at that time by an unknown mechanism). This generates a complex mixture of processing intermediates and mature products.

The key outcomes of my work were to identify all of these intermediate processing products, then produce a complete picture of FMDV polyprotein processing. Naturally, the big question was, by what mechanism did the cleavage at the C-terminus of 2A (only 18aa long) occur? Whilst at Pirbright I showed this cleavage was mediated by the 2A oligopeptide sequence alone and, latterly at St Andrews, that this was not a proteolytic event at all, but actually a translational recoding mechanism.

What qualifications did you obtain before starting this role?

I did my first degree in plant biochemistry at King’s College, London. As a full-time hedonist at that time, I did pretty badly. Working as a technician at King’s, I went on to do a part-time MSc in microbiology at Birkbeck College, London. Whilst working as a research assistant in Leicester I was offered a PhD by a newly-appointed lecturer there (Professor Jeffery Almond). As such, my fascination with viruses, particularly picornaviruses, began big time.

What are the professional challenges that present themselves and how do you try to overcome them?

Moving from a research institute (Pirbright) to a university environment (St Andrews), presented challenges in developing both teaching and a programme of independent research – and balancing time allocation between the two activities. A huge professional challenge is writing both papers and grant applications. I overcame this by learning from others; consulting experienced colleagues, reading others' (successful!) grant applications; working closely with collaborators; and asking colleagues to read drafts before I submit them. Finally, I give talks and seminars. The Microbiology Society workshops provide a superb opportunity for young researchers to hone this important skill within a friendly and supportive forum and I benefitted hugely.

What is a typical working day for you?

Whilst there is a typical mixture of activities, each day is different: undergraduate lectures, supervising undergraduate research projects, giving/attending seminars, examining theses, writing and reviewing papers, grant applications, research project management etc. It’s this mixture of responsibilities which makes the job so interesting.

Tell us about your biggest professional achievement(s) so far

For sure the development of the 2A ribosome skipping hypothesis and promoting it’s use in biomedicine and biotechnology. The model I developed, explaining how 2A works, still holds I believe, but I am fully minded of the quote: “The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact” (Thomas Huxley, 1825–1895).

Alongside this, I would rate my engagement with the government to secure permission to develop and work on the FMDV replicon (a non-infectious, biosecure form of FMDV cDNA) out with a high disease security such as Pirbright. This enabled university-based academics to collaborate more openly with Pirbright on various aspects of FMDV replication – one of the key recommendations of the Lessons to be Learned Inquiry Report following the UK 2001 outbreak.

In 2017 you were awarded the Unilever Colworth Prize by the Microbiology Society for your work on the 2A protein co-expression system. Can you tell us more about why winning this award was important to you?

Naturally, recognition from my peers and the interest and value of the work on 2A; certainly not just to me, personally, but to all of the PhD students, Postdoctoral fellows and collaborators (notably Dr Jeremy Brown, Newcastle University), who over the years contributed so substantially. I always knew there was a very interesting molecular biological story that underpinned such a simple observation and was determined to try to understand this. I knew from relatively early on that it would be an incredibly useful tool and published some papers that showcased its biotechnological utility.

Being awarded the Unilever Colworth Prize, plus others (incredible work partly facilitated by 2A) is, I admit, a source of personal pride, but also gratitude to those I mentioned above, alongside the funding bodies (Biotechnology and Biological Sciences Research Council (BBSRC); Wellcome Trust and Medical Research Council (MRC), and the reviewers who have supported my work.

You are an active member of the Microbiology Society, tell us more about your involvement.

In the past I have served on the Virology Division and the Microbiology Society’s Editorial Board. To my shame, I have not been as active as I should have been in other Society activities. My guilt is, however, assuaged somewhat by seeing so many younger researchers being brought to the fore and doing a much better job than I could have! I have always strongly exhorted my PhD students and postdocs to join the Microbiology Society, to attend meetings, meet new people and be introduced to scientists whose names they may know from publications.

Why is it important to be a member of an organisation like the Microbiology Society?

Attending Microbiology Society meetings over the years enables one to listen to fascinating lectures (by internationally renowned speakers) out with one’s immediate research interests, but also to attend Focused Meetings – a great mixture. I benefitted from receiving grants to attend meetings personally (in the olden days!) and latterly my own PhD students have done too. Importantly, these meetings enable one to meet old and make new friends – many of whom who became collaborators. Networking may have somewhat of a self-serving connotation, but I have found it to be huge fun (you get to meet a lot of very nice, very smart people) and it presents many opportunities for developing new lines of research. These meetings have been an invaluable part of my career development.

Where did your interest in microbiology come from?

My MSc in microbiology contained little virology, but I was so very lucky to be working at the University of Leicester when Jeff Almond was setting up his laboratory. At that time (the early 1980s); molecular biology was beginning to accelerate rapidly, and it was a thrill to be working in his laboratory, whilst the mutations within the poliovirus genome leading to attenuation were being determined –  some 30 years after the Salk vaccine was developed.

It’s sobering to think that my PhD (cloning and sequencing Enterovirus type 70) took me three years, but can now be accomplished in a matter of days. This was a highly formative period for me. Attending Microbiology Society meetings expanded my interests and lead to me applying for a post at the (then) Institute of Animal Health, Pirbright Laboratory. My time there enabled me to expand my interests in exotic animal viruses with a fantastic bunch of colleagues.

Why does microbiology matter?

Well, we have an all too vivid demonstration of why microbiology matters with the ongoing pandemic of coronavirus! With my work on animal viruses enabling visits to India and countries in South East Asia, one can see first-hand how viruses like FMDV and African Swine Fever (ASF) affect local farmers and national economies.

In this era of massively expanded international travel and trade – compounded by climate change – human, animal and crop pathogens rapidly transcend national borders. Indeed, in the former two cases, also species barriers. However, this is also the era of the biosciences, and microbiology matters in the development of new products, manufacturing processes, vaccines and drugs, but also in nutrition, bioremediation and the manifold roles of the microbiome within all aspects of life.

The wealth of knowledge being gained from the study of the microbial world is immense. In my case, the study of FMDV polyprotein processing led to much more efficient crop and animal transgenesis; the production of high value (therapeutic) protein products; cancer gene therapies and the production of human induced pluripotent stem cells. Who knew?

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