Inspiring Nottingham Research Fellows

Nathan Archer, Nottingham Research Fellow, School of Veterinary Medicine and Science

I am studying the earliest stages of infection and trying to understand how cells are able to sense and rapidly respond to an infection – in particular in bovine mastitis.

I hope to do this by employing cutting-edge, next-generation sequencing methodologies alongside my expertise in mRNA metabolism and the burgeoning field of the epitranscriptome.

Why did you apply for a Fellowship? 

Encouraged by my excellent experience as a PhD student at the University of Nottingham as well as my growing interaction with and encouragement by my departmental sponsors, Professors James Leigh and Nigel Mongan, I realised that the best way to get that step change towards independence, and towards a role where I could really embrace passing on knowledge to others was through the Nottingham Research Fellowship.

Why Nottingham? 

There is something special about the University of Nottingham that I first encountered as an undergraduate here, the focus on research in the student experience with not just research-active but research-invigorated academics left a real impression on me and ensures our students have a real understanding and forward-thinking approach to sciences – whatever career they ultimately choose – and I want to be a part of this. 

The support for early career researchers is excellent, both at the institutional and infrastructure levels, but also with the mentorship and support from established academics.

Finally, the facilities and infrastructure that enable me to conduct my research, combined with the knowledge that I have on-hand the expertise and the resources to maximise the impact of my research, is what cemented my decision to apply for the Nottingham Research fellowship, and I haven’t looked back.

I have found a group of people here who are fundamentally excited to find out answers to scientific questions

How have you found the Fellowship so far? 

Challenging but absolutely worth it – I am loving the experience so far. I have the independence to allow my research interests to flourish combined with a support network I can rely on to help where needed, with a clear pathway to establishing the outward facing research group I aim to establish; including the support I will need when I take on more teaching of undergraduates over the next few years.

I have found a group of people here who are fundamentally excited to find out answers to scientific questions. In my few months as a Nottingham Research Fellowship I have already been able to submit grants, foster collaborations and gain a foothold in the lab; thanks to the institutional as well as personal support for my work.

This support has helped me to identify the weak as well as strong points in my potential for grant applications. Having attended several centrally run courses for commercialisation hosted by those with direct experience in this area, I remain confident that Nottingham is the place for me and my research to flourish and have real impact.

How would you explain your research?

Our body’s cells rapidly respond to stimuli without waiting for an entirely new set of instructions to make its way from the store of DNA locked away in the nucleus of our cells. My primary expertise is in sequencing the messenger molecule responsible for carrying these instructions to the rest of the cell, mRNA, and then understanding how the metabolism of it affects cellular decision making and organism development.

The genetic alphabet is often talked about as consisting of four “letters” in DNA, with a “fifth” in RNA giving us A,C,G,T, and U. Methyl(CH3)-groups were discovered on mRNA nucleotides in the 1970s, but recent technological advancements and resulting biological insights has resulted in the field of the “epitranscriptome”. These enigmatic modifications do not appear to affect the proteins they encode, but rather the “when, where, and how” the message is used. After some impactful work on the internal mRNA modifications during my PhD followed by work examining technical and biological noise in next generation sequencing, my attention is now on the “cap adjacent” modifications found at the start of the mRNA molecule.

I am combining cutting edge sequencing methods with this paradigm-shifting view of RNA as more than “just” a messenger molecule to understand how cells can respond to infections and other stimuli. Understanding how these mechanisms go awry in infectious and developmental diseases will allow for better diagnosis and treatment. The application of this knowledge in the context of bovine mastitis enables a powerful model of early infection progression, as well as new understanding of this ethically, environmentally, and economically challenging disease.

What inspired you to pursue this area?

The field of the epitranscriptome is its infancy, often likened to the epigenetics revolution of the early 2000’s. It’s an incredibly exciting field to be a part of because as well as offering new, fundamental insights into the workings of our cells, it promises real paradigm-shifting impact in, academic, medical, and industrial arenas.

My experience of the epitranscriptome began in 2010 with my PhD – though in 2010 it was just called “mRNA methylation” and was a curiosity first noticed in the 1970s. During this PhD the field rapidly expanded, with new technologies allowing us to unravel the prevalence and consequences of internal mRNA methylation.

After a three year postdoc at the University of Warwick studying the variation in gene expression between genetically identical cells, my fascination for mRNA metabolism and modification had grown – as had my technical abilities in RNA sequencing methods – and there was still an under-explored area in mRNA methylation – the cap-adjacent modifications.  

I have found a group of people here who are fundamentally excited to find out answers to scientific questions

How will your research affect the average person?

Bovine mastitis is responsible for 80% of the UK Dairy Industry Usage of antibiotics, 1.23 million tonnes of CO2-equivalent emission per year, and a million tonnes of milk loss per year. Understanding the earliest stages of infection in this ethically, environmentally, and economically important disease has clear medium-term impact on society.

Beyond this, our society is quickly entering a biotechnology age, where genetic engineering and wider availability of cheap DNA and RNA sequencing promises improvements in our ability to read our “lottery ticket” that is our individual genetic blueprint. Understanding some of the fundamental processes used by cells to make decisions and respond to the world around us is required towards understanding what our lottery ticket really means for us.

What challenges are you hoping to tackle?

There are still some exciting fundamental questions in the epitranscriptome field, especially for the cap-adjacent modifications. For example:

• How do cells deposit, remove, and interpret these newly characterised “tags” on their messenger molecules?
• What is the impact of these on mRNA metabolism?
• And what is the impact of these changes to mRNA metabolism on cellular responses to stress, disease, and developmental programmes?

Beyond these fundamental questions, we must then explore how these new data can be used in the field, and how these exciting biological questions can translate into exciting medical or industrial tools.

What has been the greatest moment of your career so far?

It’s tough to pick a specific moment, there are several that really stick out to any researcher; my first paper published, my first lead-author paper, and having a paper published in Nature are clear highlights. One that doesn’t seem to vary between myself and my peers though, is seeing your new results for the first time – because for a short time you know something entirely new to the world.

Who or what has helped you get to where you are today?

Undoubtedly the mentorship and enthusiasm of my PhD supervisor, Professor Rupert Fray – who I continue to work with. Academic research is in many ways one of the oldest apprenticeships, and I hope that I can instil a similar sense of fundamental excitement in my own students.

I obviously would not be where I am without my parents, either, allowing me to take things apart as a child (and understanding when I couldn’t always reassemble them).

With the support of these people, and the new colleagues in the School of Veterinary Medicine – in particular Professors James Leigh and Nigel Mongan, I really am excited to where this fellowship leads!

Beyond this, a combination of a few late nights, good coffee, and a lot of luck.  

What advice would you give to someone starting out?

Luck is important, but the more you read and the more open you are to discuss, help and teach people, the more luck seems to appear..! Find some good mentors who believe in your ability beyond your last successful (or failed) experiment!

Hard work is important, but so is making time for avoiding work altogether, try not to feel guilty when you’re on some hard-won downtime, your brain will still be working on solutions to your problems.

What next?

I am still in the early stages of an independent research career. I am very excited to uncover the role of cap-adjacent methylation in mRNA metabolism, and the role of these modifications in responses to the environment. I am really excited to see some of the novel insights we have unearthed be published soon.  

Beyond these scientific questions, I am embracing the opportunity to build a vibrant and collaborative research lab, so that I can pass on some of the excitement for mRNA biochemistry and fundamental research that was once ignited in me.

In the long term I’d love to see the insights and mechanistic understanding of the epitranscriptome that I have contributed to make its way into mainstream industry and medicine – when I started my PhD in mRNA methylation in September 2010, the epitranscriptome didn’t even have its moniker, and was often considered “blue sky” research. There is great satisfaction in seeing this field reaching a promising adolescence.

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Feeling inspired?